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Parkinson Disease: HELP
Articles by Yunjong Lee
Based on 26 articles published since 2010
(Why 26 articles?)
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Between 2010 and 2020, Yunjong Lee wrote the following 26 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin From Radix Glycyrrhizae in Human Health and Disease Models. 2018

Ramalingam, Mahesh / Kim, Hyojung / Lee, Yunjong / Lee, Yun-Il. ·Well Aging Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea. · Companion Diagnostics and Medical Technology Research Group, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea. ·Front Aging Neurosci · Pubmed #30443212.

ABSTRACT: The increasing lifespan in developed countries results in age-associated chronic diseases. Biological aging is a complex process associated with accumulated cellular damage by environmental or genetic factors with increasing age. Aging results in marked changes in brain structure and function. Age-related neurodegenerative diseases and disorders (NDDs) represent an ever-growing socioeconomic challenge and lead to an overall reduction in quality of life around the world. Alzheimer's disease (AD) and Parkinson's disease (PD) are most common degenerative neurological disorders of the central nervous system (CNS) in aging process. The low levels of acetylcholine and dopamine are major neuropathological feature of NDDs in addition to oxidative stress, intracellular calcium ion imbalance, mitochondrial dysfunction, ubiquitin-proteasome system impairment and endoplasmic reticulum stress. Current treatments minimally influence these diseases and are ineffective in curing the multifunctional pathological mechanisms. Synthetic neuroprotective agents sometimes have negative reactions as an adverse effect in humans. Recently, numerous ethnobotanical studies have reported that herbal medicines for the treatment or prevention of NDDs are significantly better than synthetic drug treatment. Medicinal herbs have traditionally been used around the world for centuries. Radix Glycyrrhizae (RG) is the dried roots and rhizomes of

2 Review Poly (ADP-ribose) in the pathogenesis of Parkinson's disease. 2014

Lee, Yunjong / Kang, Ho Chul / Lee, Byoung Dae / Lee, Yun-Il / Kim, Young Pil / Shin, Joo-Ho. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering; Departments of Physiology, and Neurology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering; Departments of Neurology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Ajou University School of Medicine, Suwon 443-721, Korea. · Neurodegeneration Control Research Center, Department of Neuroscience, Kyung Hee University, Seoul 130-701, Korea. · Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon 443-803, Korea. · Department of Bio-Engineering, Life Science RD Center, Sinil Pharmaceutical Co., Seoul 462-807, Korea. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering; Departments of Neurology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, Korea. ·BMB Rep · Pubmed #24874851.

ABSTRACT: The defining feature of Parkinson's disease is a progressive and selective demise of dopaminergic neurons. A recent report on Parkinson's disease animal model demonstrates that poly (ADP-ribose) (PAR) dependent cell death, also named parthanatos, is accountable for selective dopaminergic neuronal loss. Parthanatos is a programmed necrotic cell death, characterized by PARP1 activation, apoptosis inducing factor (AIF) nuclear translocation, and large scale DNA fragmentation. Besides cell death regulation via interaction with AIF, PAR molecule mediates diverse cellular processes including genomic stability, cell division, transcription, epigenetic regulation, and stress granule formation. In this review, we will discuss the roles of PARP1 activation and PAR molecules in the pathological processes of Parkinson's disease. Potential interaction between PAR molecule and Parkinson's disease protein interactome are briefly introduced. Finally, we suggest promising points of therapeutic intervention in the pathological PAR signaling cascade to halt progression in Parkinson's disease.

3 Review Animal models of Parkinson's disease: vertebrate genetics. 2012

Lee, Yunjong / Dawson, Valina L / Dawson, Ted M. ·NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ·Cold Spring Harb Perspect Med · Pubmed #22960626.

ABSTRACT: Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed.

4 Article Deubiquitinase USP29 Governs MYBBP1A in the Brains of Parkinson's Disease Patients. 2019

Jo, Areum / Lee, Yunjong / Park, Chi-Hu / Shin, Joo-Ho. ·Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea. · Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon 16419, Korea. · Samsung Biomedical Research Institute, Samsung Medical Center, Seoul 06351, Korea. · Natural Bioactive & Anticancer Research Institute, YEPBio Co., Ltd., Suwon 16229, Korea. ·J Clin Med · Pubmed #31878357.

ABSTRACT: The inactivation of parkin by mutation or post-translational modification contributes to dopaminergic neuronal death in Parkinson's disease (PD). The substrates of parkin, FBP1 and AIMP2, are accumulated in the postmortem brains of PD patients, and it was recently suggested that these parkin substrates transcriptionally activate deubiquitinase

5 Article Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson's Disease. 2019

Ham, Sangwoo / Kim, Heejeong / Yoon, Jin-Ha / Kim, Hyojung / Song, Bo Reum / Choi, Jeong-Yun / Lee, Yun-Song / Paek, Seung-Mann / Maeng, Han-Joo / Lee, Yunjong. ·Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea. ham89p12@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea. kimhj9301@gmail.com. · College of Pharmacy, Gachon University, Incheon 21936, Korea. jinha89@daum.net. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea. hjung93@skku.edu. · College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju Daero 501, Jinju 52828, Gyeongnam, Korea. qhfma2005@naver.com. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea. choijy@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea. yslee@skku.edu. · College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju Daero 501, Jinju 52828, Gyeongnam, Korea. million@gnu.ac.kr. · College of Pharmacy, Gachon University, Incheon 21936, Korea. hjmaeng@gachon.ac.kr. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 16419, Korea. ylee69@skku.edu. ·Int J Mol Sci · Pubmed #31689937.

ABSTRACT: The motor and nonmotor symptoms of Parkinson's disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII's neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.

6 Article Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease. 2019

Brahmachari, Saurav / Lee, Saebom / Kim, Sangjune / Yuan, Changqing / Karuppagounder, Senthilkumar S / Ge, Preston / Shi, Rosa / Kim, Esther J / Liu, Alex / Kim, Donghoon / Quintin, Stephan / Jiang, Haisong / Kumar, Manoj / Yun, Seung Pil / Kam, Tae-In / Mao, Xiaobo / Lee, Yunjong / Swing, Deborah A / Tessarollo, Lino / Ko, Han Seok / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ·Brain · Pubmed #31237944.

ABSTRACT: α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson's disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson's disease, there is evidence that parkin is inactivated in sporadic Parkinson's disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson's disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson's disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson's disease and related α-synucleinopathies.

7 Article Rhododendrin-Induced RNF146 Expression via Estrogen Receptor β Activation is Cytoprotective Against 6-OHDA-Induced Oxidative Stress. 2019

Kim, Hyojung / Park, Jisoo / Leem, HyunHee / Cho, MyoungLae / Yoon, Jin-Ha / Maeng, Han-Joo / Lee, Yunjong. ·Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. hjung93@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. zysu0728@skku.edu. · National Development Institute of Korean Medicine, Gyeongsan 38540, Korea. npb0391@nikom.or.kr. · National Development Institute of Korean Medicine, Gyeongsan 38540, Korea. meanglae@nikom.or.kr. · College of Pharmacy, Gachon University, Incheon 21936, Korea. jinha89@daum.net. · College of Pharmacy, Gachon University, Incheon 21936, Korea. hjmaeng@gachon.ac.kr. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. ylee69@skku.edu. ·Int J Mol Sci · Pubmed #30974833.

ABSTRACT: Ring finger protein 146 (RNF146) is an E3 ubiquitin ligase whose activity prevents poly (ADP-ribose) polymerase 1 (PARP1)-dependent neurodegeneration in Parkinson's disease (PD). Previously, we reported that rhododendrin is a chemical inducer that increases RNF146 expression. However, the molecular mechanism of rhododendrin-induced RNF146 expression is largely unknown and its translational application for the treatment of Parkinson's disease remains unexplored. Here we found that rhododendrin increased RNF146 expression via estrogen receptor β (ERβ) activation. Rhododendrin stimulated ERβ nuclear translocation and binding to the RNF146 promoter, thereby enhancing its transcription. Rhododendrin is cytoprotective against 6-hydroxydopamine (6-OHDA)-induced cell death, which is largely dependent on ERβ activity and RNF146 expression. Finally, we demonstrated that rhododendrin treatment resulted in RNF146 expression in dopaminergic neurons in mice. Moreover, dopaminergic neuron viability was markedly enhanced by pretreatment with rhododendrin in 6-OHDA-induced mouse models for PD. Our findings indicate that estrogen receptor activation plays a neuroprotective role and that rhododendrin could be a potential therapeutic agent in preventing PARP1-dependent dopaminergic cell loss in PD.

8 Article Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. 2018

Yun, Seung Pil / Kam, Tae-In / Panicker, Nikhil / Kim, SangMin / Oh, Yumin / Park, Jong-Sung / Kwon, Seung-Hwan / Park, Yong Joo / Karuppagounder, Senthilkumar S / Park, Hyejin / Kim, Sangjune / Oh, Nayeon / Kim, Nayoung Alice / Lee, Saebom / Brahmachari, Saurav / Mao, Xiaobo / Lee, Jun Hee / Kumar, Manoj / An, Daniel / Kang, Sung-Ung / Lee, Yunjong / Lee, Kang Choon / Na, Dong Hee / Kim, Donghoon / Lee, Sang Hun / Roschke, Viktor V / Liddelow, Shane A / Mari, Zoltan / Barres, Ben A / Dawson, Valina L / Lee, Seulki / Dawson, Ted M / Ko, Han Seok. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. · The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. · College of Pharmacy, Sungkyunkwan University, Suwon, South Korea. · College of Pharmacy, Chung-Ang University, Seoul, South Korea. · Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Seoul Hospital, Seoul, South Korea. · Neuraly Inc, Baltimore, MD, USA. · Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA, USA. · The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. slee343@jhmi.edu. · The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. slee343@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu. · Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. tdawson@jhmi.edu. · Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu. · Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. tdawson@jhmi.edu. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. tdawson@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. hko3@jhmi.edu. · Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. hko3@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. hko3@jhmi.edu. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. hko3@jhmi.edu. ·Nat Med · Pubmed #29892066.

ABSTRACT: Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases

9 Article Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice. 2018

Xiong, Yulan / Neifert, Stewart / Karuppagounder, Senthilkumar S / Liu, Qinfang / Stankowski, Jeannette N / Lee, Byoung Dae / Ko, Han Seok / Lee, Yunjong / Grima, Jonathan C / Mao, Xiaobo / Jiang, Haisong / Kang, Sung-Ung / Swing, Deborah A / Iacovitti, Lorraine / Tessarollo, Lino / Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205; yulanxiong@ksu.edu vdawson@jhmi.edu tdawson@jhmi.edu. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685. · Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702. · Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107. · Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205. ·Proc Natl Acad Sci U S A · Pubmed #29386392.

ABSTRACT: Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson's disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons. Accompanying the loss of DA neurons are DA-dependent behavioral deficits and α-synuclein pathology that are also LRRK2 GS kinase-dependent. Transmission EM reveals that that there is an LRRK2 GS kinase-dependent significant reduction in synaptic vesicle number and a greater abundance of clathrin-coated vesicles in DA neurons. These transgenic mice indicate that LRRK2-induced DA and NE neurodegeneration is kinase-dependent and can occur in a cell-autonomous manner. Moreover, these mice provide a substantial advance in animal model development for LRRK2-associated PD and an important platform to investigate molecular mechanisms for how DA neurons degenerate as a result of expression of mutant LRRK2.

10 Article α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism. 2018

Yun, Seung Pil / Kim, Donghoon / Kim, Sangjune / Kim, SangMin / Karuppagounder, Senthilkumar S / Kwon, Seung-Hwan / Lee, Saebom / Kam, Tae-In / Lee, Suhyun / Ham, Sangwoo / Park, Jae Hong / Dawson, Valina L / Dawson, Ted M / Lee, Yunjong / Ko, Han Seok. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Neurology, Baltimore, MD, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. · Department of Physiology, Baltimore, MD, USA. · Solomon H. Snyder Department of Neuroscience, Baltimore, MD, USA. · Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. ylee69@skku.edu. · Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. ylee69@skku.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. hko3@jhmi.edu. · Department of Neurology, Baltimore, MD, USA. hko3@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. hko3@jhmi.edu. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. hko3@jhmi.edu. ·Mol Neurodegener · Pubmed #29310663.

ABSTRACT: BACKGROUND: Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA METHOD: We used GBA RESULTS: L444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of α-synuclein in the midbrain of GBA CONCLUSION: Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and α-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP.

11 Article PARIS reprograms glucose metabolism by HIF-1α induction in dopaminergic neurodegeneration. 2018

Kang, Hojin / Jo, Areum / Kim, Hyein / Khang, Rin / Lee, Ji-Yeong / Kim, Hanna / Park, Chi-Hu / Choi, Jeong-Yun / Lee, Yunjong / Shin, Joo-Ho. ·Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea; Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. · HuGeX Co., Ltd. Seongnam, 462-122, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea; Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. Electronic address: jshin24@skku.edu. ·Biochem Biophys Res Commun · Pubmed #29287724.

ABSTRACT: Our previous study found that PARIS (ZNF746) transcriptionally suppressed transketolase (TKT), a key enzyme in pentose phosphate pathway (PPP) in the substantia nigra (SN) of AAV-PARIS injected mice. In this study, we revealed that PARIS overexpression reprogrammed glucose metabolic pathway, leading to the increment of glycolytic proteins along with TKT reduction in the SN of AAV-PARIS injected mice. Knock-down of TKT in differentiated SH-SY5Y cells led to an increase of glycolytic enzymes and decrease of PPP-related enzymes whereas overexpression of TKT restored PARIS-mediated glucose metabolic shift, suggesting that glucose metabolic alteration by PARIS is TKT-dependent. Inhibition of PPP by either PARIS overexpression or TKT knock-down elevated the level of H

12 Article CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation. 2017

Kim, Hyojung / Ham, Sangwoo / Jo, Minkyung / Lee, Gum Hwa / Lee, Yun-Song / Shin, Joo-Ho / Lee, Yunjong. ·Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. hjung93@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. ham89p12@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. jmk4606@naver.com. · College of Pharmacy, Chosun University, Gwangju 501-759, Korea. yslee@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. gumhwalee@chosun.ac.kr. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. jshin24@skku.edu. · Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, Korea. jshin24@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Gyeonggi-do 440-746, Korea. ylee69@skku.edu. ·Int J Mol Sci · Pubmed #28972555.

ABSTRACT: Aging is considered the major risk factor for neurodegenerative diseases including Parkinson's disease (PD). Telomere shortening is associated with cellular senescence. In this regard, pharmacological or genetic inhibition of telomerase activity has been used to model cellular aging. Here, we employed CRISPR-Cas9 technology to instantly remove the telomere to induce aging in a neuroblastoma cell line. Expression of both Cas9 and guide RNA targeting telomere repeats ablated the telomere, leading to retardation of cell proliferation. Instant deletion of telomere in SH-SY5Y cells impaired mitochondrial function with diminished mitochondrial respiration and cell viability. Supporting the pathological relevance of cell aging by CRISPR-Cas9 mediated telomere removal, alterations were observed in the levels of PD-associated proteins including PTEN-induced putative kinase 1, peroxisome proliferator-activated receptor γ coactivator 1-α, nuclear respiratory factor 1, parkin, and aminoacyl tRNA synthetase complex interacting multifunctional protein 2. Significantly, α-synuclein expression in the background of telomere removal led to the enhancement of protein aggregation, suggesting positive feed-forward interaction between aging and PD pathogenesis. Collectively, our results demonstrate that CRISPR-Cas9 can be used to efficiently model cellular aging and PD.

13 Article Identification of transketolase as a target of PARIS in substantia nigra. 2017

Kim, Hyein / Kang, Hojin / Lee, Yunjong / Park, Chi-Hu / Jo, Areum / Khang, Rin / Shin, Joo-Ho. ·Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea; HuGeX Co., Ltd., Seongnam 462-122, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea; Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. · HuGeX Co., Ltd., Seongnam 462-122, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea; Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. Electronic address: jshin24@skku.edu. ·Biochem Biophys Res Commun · Pubmed #28939041.

ABSTRACT: Recently, PARIS (ZNF746) is introduced as authentic substrate of parkin and transcriptionally represses PGC-1α by binding to insulin responsive sequences (IRSs) in the promoter of PGC-1α. The overexpression of PARIS selectively leads to the loss of dopaminergic neurons (DN) and mitochondrial abnormalities in the substantia nigra (SN) of Parkinson's disease (PD) models. To identify PARIS target molecules altered in SN region-specific manner, LC-MS/MS-based quantitative proteomic analysis is employed to investigate proteomic alteration in the cortex, striatum, and SN of AAV-PARIS injected mice. Herein, we find that the protein and mRNA of transketolase (TKT), a key enzyme in pentose phosphate pathway (PPP) of glucose metabolism, is exclusively decreased in the SN of AAV-PARIS mice. PARIS overexpression suppresses TKT transcription via IRS-like motif in the TKT promoter. Moreover, the reduction of TKT by PARIS is found in primary DN but not in cortical neurons, suggesting that PARIS-medicated TKT suppression is cell type-dependent. Interestingly, we observe the reduced level of TKT in the SN of PD patients but not in the cortex. These findings indicate that TKT might be a SN-specific target of PARIS, providing new clues to understand the mechanism underlying selective DNs death in PD.

14 Article Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection. 2017

Kang, Hojin / Khang, Rin / Ham, Sangwoo / Jeong, Ga Ram / Kim, Hyojung / Jo, Minkyung / Lee, Byoung Dae / Lee, Yun Il / Jo, Areum / Park, ChiHu / Kim, Hyein / Seo, Jeongkon / Paek, Sun Ha / Lee, Yun-Song / Choi, Jeong-Yun / Lee, Yunjong / Shin, Joo-Ho. ·Department of Molecular Cell Biology, Division of Pharmacology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. · Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, South Korea. · Department of Neuroscience, Department of Physiology, Neurodegeneration Control Research Center, Kyung Hee University School of Medicine, Seoul, South Korea. · Department of New Biology, Daegu Geongbuk Institute of Science and Technology, Daegu, South Korea. · Research Core Facility, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. · HuGeX Co., Ltd. Seongnam, South Korea. · UNIST Central Research Facility, Ulsan National Institute of Science and Technology, Ulsan, South Korea. · Department of Neurosurgery, Seoul National University College of Medicine, Seoul, South Korea. ·Oncotarget · Pubmed #28611284.

ABSTRACT: Progressive dopaminergic neurodegeneration is responsible for the canonical motor deficits in Parkinson's disease (PD). The widely prescribed anti-diabetic medicine metformin is effective in preventing neurodegeneration in animal models; however, despite the significant potential of metformin for treating PD, the therapeutic effects and molecular mechanisms underlying dopaminergic neuroprotection by metformin are largely unknown.In this study, we found that metformin induced substantial proteomic changes, especially in metabolic and mitochondrial pathways in the substantia nigra (SN). Consistent with this data, metformin increased mitochondrial marker proteins in SH-SY5Y neuroblastoma cells. Mitochondrial protein expression by metformin was found to be brain region specific, with metformin increasing mitochondrial proteins in the SN and the striatum, but not the cortex. As a potential upstream regulator of mitochondria gene transcription by metformin, PGC-1α promoter activity was stimulated by metformin via CREB and ATF2 pathways. PGC-1α and phosphorylation of ATF2 and CREB by metformin were selectively increased in the SN and the striatum, but not the cortex. Finally, we showed that metformin protected dopaminergic neurons and improved dopamine-sensitive motor performance in an MPTP-induced PD animal model. Together these results suggest that the metformin-ATF2/CREB-PGC-1α pathway might be promising therapeutic target for PD.

15 Article VPS35 regulates parkin substrate AIMP2 toxicity by facilitating lysosomal clearance of AIMP2. 2017

Yun, Seung Pil / Kim, Hyojung / Ham, Sangwoo / Kwon, Seung-Hwan / Lee, Gum Hwa / Shin, Joo-Ho / Lee, Sang Hun / Ko, Han Seok / Lee, Yunjong. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea. · College of Pharmacy, Chosun University, Gwangju, Republic of Korea. · Medical Science Research Institute, Soonchunhyang University, Seoul Hospital, Seoul, Republic of Korea. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. ·Cell Death Dis · Pubmed #28383562.

ABSTRACT: Vacuolar protein sorting-associated protein 35 (VPS35) is involved in retrograde transport of proteins from endosomes to trans-Golgi network. Gene mutations in VPS35 are linked to autosomal dominant late-onset Parkinson's disease (PD). Although the identification of VPS35 mutations has provided novel insight about its interactions with several PD-associated genes including leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, little information is available about the molecular mechanisms of cell death downstream of VPS35 dysfunction. In this study, we showed that VPS35 has a role in the lysosomal degradation of parkin substrate aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2), of which accumulation leads to poly(ADP-ribose) polymerase-1 (PARP1)-dependent cell death. VPS35 was co-immunoprecipitated with AIMP2, as well as lysosome-associated membrane protein-2a (Lamp2a). Interestingly, this association was disrupted by PD-associated VPS35 mutant D620N. VPS35 overexpression prevented AIMP2-potentiated cell death and PARP1 activation in SH-SY5Y cells. More importantly, knockdown of VPS35 led to PARP1 activation and cell death, which was AIMP2 dependent. These findings provide new mechanistic insights into the role of VPS35 in the regulation of AIMP2 levels and cell death. As AIMP2 accumulation was reported in PD patient's brains and involved in dopaminergic cell death, identification of VPS35 as a novel regulator of AIMP2 clearance via lysosomal pathway provides alternative venue to control dopaminergic cell death in PD.

16 Article Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson's disease model. 2017

Ham, Sangwoo / Lee, Yun-Il / Jo, Minkyung / Kim, Hyojung / Kang, Hojin / Jo, Areum / Lee, Gum Hwa / Mo, Yun Jeong / Park, Sang Chul / Lee, Yun Song / Shin, Joo-Ho / Lee, Yunjong. ·Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea. · Well Aging Research Center, DGIST, Daegu, 42988, Republic of Korea. ylee56@dgist.ac.kr. · Companion Diagnostics and Medical Technology Research Group, DGIST, Daegu, 42988, Republic of Korea. ylee56@dgist.ac.kr. · College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea. · Well Aging Research Center, DGIST, Daegu, 42988, Republic of Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea. jshin24@skku.edu. · Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea. jshin24@skku.edu. · Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, 440-746, Republic of Korea. ylee69@skku.edu. ·Sci Rep · Pubmed #28366931.

ABSTRACT: Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson's disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. Here we performed an unbiased high-throughput luciferase screening to identify chemicals that can increase parkin expression. Among promising parkin inducers, hydrocortisone possessed the most favorable profiles including parkin induction ability, cell protection ability, and physicochemical property of absorption, distribution, metabolism, and excretion (ADME) without inducing endoplasmic reticulum stress. We found that hydrocortisone-induced parkin expression was accountable for cell protection against oxidative stress. Hydrocortisone-activated parkin expression was mediated by CREB pathway since gRNA to CREB abolished hydrocortisone's ability to induce parkin. Finally, hydrocortisone treatment in mice increased brain parkin levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin's injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway and the induced parkin expression was accountable for its neuroprotective effect. Since glucocorticoid is a physiological hormone, maintaining optimal levels of glucocorticoid might be a potential therapeutic or preventive strategy for Parkinson's disease.

17 Article Overexpression of Parkinson's Disease-Associated Mutation LRRK2 G2019S in Mouse Forebrain Induces Behavioral Deficits and α-Synuclein Pathology. 2017

Xiong, Yulan / Neifert, Stewart / Karuppagounder, Senthilkumar S / Stankowski, Jeannette N / Lee, Byoung Dae / Grima, Jonathan C / Chen, Guanxing / Ko, Han Seok / Lee, Yunjong / Swing, Debbie / Tessarollo, Lino / Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Anatomy and Physiology, Kansas State University College of Veterinary Medicine, Manhattan, Kansas 66506. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Soloman H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Department of Anatomy and Physiology, Kansas State University College of Veterinary Medicine , Manhattan, Kansas 66506. · Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Soloman H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Soloman H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130. ·eNeuro · Pubmed #28321439.

ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an unambiguous cause of late-onset, autosomal-dominant familial Parkinson's disease (PD) and LRRK2 mutations are the strongest genetic risk factor for sporadic PD known to date. A number of transgenic mice expressing wild-type or mutant LRRK2 have been described with varying degrees of LRRK2-related abnormalities and modest pathologies. None of these studies directly addressed the role of the kinase domain in the changes observed and none of the mice present with robust features of the human disease. In an attempt to address these issues, we created a conditional LRRK2 G2019S (LRRK2 GS) mutant and a functionally negative control, LRRK2 G2019S/D1994A (LRRK2 GS/DA). Expression of LRRK2 GS or LRRK2 GS/DA was conditionally controlled using the tet-off system in which the presence of tetracycline-transactivator protein (tTA) with a CAMKII

18 Article PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival. 2017

Lee, Yunjong / Stevens, Daniel A / Kang, Sung-Ung / Jiang, Haisong / Lee, Yun-Il / Ko, Han Seok / Scarffe, Leslie A / Umanah, George E / Kang, Hojin / Ham, Sangwoo / Kam, Tae-In / Allen, Kathleen / Brahmachari, Saurav / Kim, Jungwoo Wren / Neifert, Stewart / Yun, Seung Pil / Fiesel, Fabienne C / Springer, Wolfdieter / Dawson, Valina L / Shin, Joo-Ho / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, FL 32224, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. Electronic address: vdawson@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea. Electronic address: jshin24@skku.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. Electronic address: tdawson@jhmi.edu. ·Cell Rep · Pubmed #28122242.

ABSTRACT: Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson's disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. PINK1 phosphorylation of PARIS alleviates PARIS toxicity, as well as repression of PGC-1α promoter activity. Conditional knockdown of PINK1 in adult mouse brains leads to a progressive loss of dopaminergic neurons in the substantia nigra that is dependent on PARIS. Altogether, these results uncover a function of PINK1 to direct parkin-PARIS-regulated PGC-1α expression and dopaminergic neuronal survival.

19 Article Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons. 2016

Jiang, Haisong / Kang, Sung-Ung / Zhang, Shuran / Karuppagounder, Senthilkumar / Xu, Jinchong / Lee, Yong-Kyu / Kang, Bong-Gu / Lee, Yunjong / Zhang, Jianmin / Pletnikova, Olga / Troncoso, Juan C / Pirooznia, Shelia / Andrabi, Shaida A / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685. · Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130-2685; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. ·eNeuro · Pubmed #27622213.

ABSTRACT: Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated a role for peroxisome proliferator-activated receptor γ coactivator protein-1α (PGC-1α) in PD and in animal or cellular models of PD. The role of PGC-1α in the function and survival of substantia nigra pars compacta (SNpc) dopamine neurons is not clear. Here we find that there are four different PGC-1α isoforms expressed in SH-SY5Y cells, and these four isoforms are expressed across subregions of mouse brain. Adult conditional PGC-1α knock-out mice show a significant loss of dopaminergic neurons that is accompanied by a reduction of dopamine in the striatum. In human PD postmortem tissue from the SNpc, there is a reduction of PGC-1α isoforms and mitochondria markers. Our findings suggest that all four isoforms of PGC-1α are required for the proper expression of mitochondrial proteins in SNpc DA neurons and that PGC-1α is essential for SNpc DA neuronal survival, possibly through the maintenance of mitochondrial function.

20 Article Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. 2016

Brahmachari, Saurav / Ge, Preston / Lee, Su Hyun / Kim, Donghoon / Karuppagounder, Senthilkumar S / Kumar, Manoj / Mao, Xiaobo / Shin, Joo Ho / Lee, Yunjong / Pletnikova, Olga / Troncoso, Juan C / Dawson, Valina L / Dawson, Ted M / Ko, Han Seok. · ·J Clin Invest · Pubmed #27348587.

ABSTRACT: Aggregation of α-synuclein contributes to the formation of Lewy bodies and neurites, the pathologic hallmarks of Parkinson disease (PD) and α-synucleinopathies. Although a number of human mutations have been identified in familial PD, the mechanisms that promote α-synuclein accumulation and toxicity are poorly understood. Here, we report that hyperactivity of the nonreceptor tyrosine kinase c-Abl critically regulates α-synuclein-induced neuropathology. In mice expressing a human α-synucleinopathy-associated mutation (hA53Tα-syn mice), deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Conversely, overexpression of constitutively active c-Abl in hA53Tα-syn mice accelerated α-synuclein aggregation, neuropathology, and neurobehavioral deficits. Moreover, c-Abl activation led to an age-dependent increase in phosphotyrosine 39 α-synuclein. In human postmortem samples, there was an accumulation of phosphotyrosine 39 α-synuclein in brain tissues and Lewy bodies of PD patients compared with age-matched controls. Furthermore, in vitro studies show that c-Abl phosphorylation of α-synuclein at tyrosine 39 enhances α-synuclein aggregation. Taken together, this work establishes a critical role for c-Abl in α-synuclein-induced neurodegeneration and demonstrates that selective inhibition of c-Abl may be neuroprotective. This study further indicates that phosphotyrosine 39 α-synuclein is a potential disease indicator for PD and related α-synucleinopathies.

21 Article Diaminodiphenyl sulfone-induced parkin ameliorates age-dependent dopaminergic neuronal loss. 2016

Lee, Yun-Il / Kang, Hojin / Ha, Young Wan / Chang, Ki-Young / Cho, Sung-Chun / Song, Sang Ok / Kim, Hyein / Jo, Areum / Khang, Rin / Choi, Jeong-Yun / Lee, Yunjong / Park, Sang Chul / Shin, Joo-Ho. ·Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea; Well Aging Research Center, Daegu Geongbuk Institute of Science and Technology (DGIST), Daegu, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea. · Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea. · Well Aging Research Center, Samsung Advanced Institute of Technology (SAIT), Suwon, South Korea; Department of New Biology, Daegu Geongbuk Institute of Science and Technology (DGIST), Daegu, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea. Electronic address: jshin24@skku.edu. ·Neurobiol Aging · Pubmed #27103513.

ABSTRACT: During normal aging, the number of dopaminergic (DA) neurons in the substantia nigra progressively diminishes, although massive DA neuronal loss is a hallmark sign of Parkinson's disease. Unfortunately, there is little known about the molecular events involved in age-related DA neuronal loss. In this study, we found that (1) the level of parkin was decreased in the cerebellum, brain stem, substantia nigra, and striatum of aged mice, (2) diaminodiphenyl sulfone (DDS) restored the level of parkin, (3) DDS prevented age-dependent DA neuronal loss, and (4) DDS protected SH-SY5Y cells from 1-methyl-4-phenylpyridinium and hydrogen peroxide. Furthermore, pretreatment and/or post-treatment of DDS in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease model attenuated DA neuronal loss and restored motor behavior. DDS transcriptionally activated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 signaling and DDS not only failed to induce parkin expression but also failed to rescue SH-SY5Y cells from 1-methyl-4-phenylpyridinium in the absence of ATF4. Herein, we demonstrated for the first time that DDS increased parkin level and served as a neuroprotective agent for age-dependent DA neuronal loss. Thus, DDS may be a potential therapeutic agent for age-related neurodegeneration.

22 Article LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. 2016

Karuppagounder, Senthilkumar S / Xiong, Yulan / Lee, Yunjong / Lawless, Maeve C / Kim, Donghyun / Nordquist, Emily / Martin, Ian / Ge, Preston / Brahmachari, Saurav / Jhaldiyal, Aanishaa / Kumar, Manoj / Andrabi, Shaida A / Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Biological Science, Louisiana State University, Baton Rouge, LA 70803, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Krieger School of Arts and Sciences, Department of Molecular and Cellular Biology, Johns Hopkins University, Baltimore MD 21218, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA. Electronic address: tdawson@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA USA. Electronic address: vdawson@jhmi.edu. ·J Chem Neuroanat · Pubmed #26808467.

ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of late onset autosomal dominant form of Parkinson disease (PD). Gain of kinase activity due to the substitution of Gly 2019 to Ser (G2019S) is the most common mutation in the kinase domain of LRRK2. Genetic predisposition and environmental toxins contribute to the susceptibility of neurodegeneration in PD. To identify whether the genetic mutations in LRRK2 increase the susceptibility to environmental toxins in PD models, we exposed transgenic mice expressing human G2019S mutant or wild type (WT) LRRK2 to the environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment resulted in a greater loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta (SNpc) in LRRK2 G2019S transgenic mice compared to the LRRK2 WT overexpressing mice. Similarly loss of dopamine levels were greater in the striatum of LRRK2 G2019S mice when compared to the LRRK2 WT mice when both were treated with MPTP. This study suggests a likely interaction between genetic and environmental risk factors in the PD pathogenesis and that the G2019S mutation in LRRK2 increases the susceptibility of dopamine neurons to PD-causing toxins.

23 Article Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration. 2015

Stevens, Daniel A / Lee, Yunjong / Kang, Ho Chul / Lee, Byoung Dae / Lee, Yun-Il / Bower, Aaron / Jiang, Haisong / Kang, Sung-Ung / Andrabi, Shaida A / Dawson, Valina L / Shin, Joo-Ho / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 446-746, South Korea; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Physiology, Ajou University School of Medicine, Suwon 443-721, Korea; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Age-Related and Brain Disease Research Center, Department of Neuroscience, Kyung Hee University, Seoul, 130-701, South Korea; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Well Aging Research Center, Samsung Advanced Institute of Technology, Yongin-si 446-712, Korea; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 446-746, South Korea; tdawson@jhmi.edu jshin24@skku.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 tdawson@jhmi.edu jshin24@skku.edu. ·Proc Natl Acad Sci U S A · Pubmed #26324925.

ABSTRACT: Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.

24 Article The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. 2014

Karuppagounder, Senthilkumar S / Brahmachari, Saurav / Lee, Yunjong / Dawson, Valina L / Dawson, Ted M / Ko, Han Seok. ·1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [4] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [4] Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [5] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [4] Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [5] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA [6]. · 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA [4]. ·Sci Rep · Pubmed #24786396.

ABSTRACT: c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.

25 Article PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. 2011

Shin, Joo-Ho / Ko, Han Seok / Kang, Hochul / Lee, Yunjong / Lee, Yun-Il / Pletinkova, Olga / Troconso, Juan C / Dawson, Valina L / Dawson, Ted M. ·NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ·Cell · Pubmed #21376232.

ABSTRACT: A hallmark of Parkinson's disease (PD) is the preferential loss of substantia nigra dopamine neurons. Here, we identify a new parkin interacting substrate, PARIS (ZNF746), whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human PD brain. PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons in a PARIS-dependent manner. Moreover, overexpression of PARIS leads to the selective loss of DA neurons in the substantia nigra, and this is reversed by either parkin or PGC-1α coexpression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

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