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Parkinson Disease: HELP
Articles by Byoung Dae Lee
Based on 16 articles published since 2010
(Why 16 articles?)
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Between 2010 and 2020, Byoung D. Lee wrote the following 16 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Review Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson's disease and beyond. 2015

Bae, Jae Ryul / Lee, Byoung Dae. ·Department of Neuroscience, of Medicine, Kyung Hee University, Seoul 130-701, Korea. · Department of Neuroscience; Neurodegeneration Control Research Center; Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea. ·BMB Rep · Pubmed #25703537.

ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). As such, functions and dysfunctions of LRRK2 in PD have been the subject of extensive investigation. In addition to PD, increasing evidence is suggesting that LRRK2 is associated with a wide range of diseases. Genome-wide association studies have implicated LRRK2 in Crohn's disease (CD) and leprosy, and the carriers with pathogenic mutations of LRRK2 show increased risk to develop particular types of cancer. LRRK2 mutations are rarely found in Alzheimer's disease (AD), but LRRK2 might play a part in tauopathies. The association of LRRK2 with the pathogenesis of apparently unrelated diseases remains enigmatic, but it might be related to the yet unknown diverse functions of LRRK2. Here, we reviewed current knowledge on the link between LRRK2 and several diseases, including PD, AD, CD, leprosy, and cancer, and discussed the possibility of targeting LRRK2 in such diseases.

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 Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease. 2012

Lee, Byoung Dae / Dawson, Valina L / Dawson, Ted M. ·Age-Related and Brain Disease Research Center, Kyung Hee University, Seoul, South Korea. ·Trends Pharmacol Sci · Pubmed #22578536.

ABSTRACT: Parkinson's disease (PD) is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra. Although the etiology for most PD remains elusive, the identification of specific genetic defects in familial cases of PD and the signaling pathways governed by these genes has provided tremendous insight into PD pathogenesis. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequently found in familial and sporadic PD. Although current knowledge regarding the regulatory mechanisms of LRRK2 activation is limited, it is becoming increasingly evident that aberrant kinase activity of the pathologic mutants of LRRK2 is associated with neurodegeneration, suggesting that the kinase activity of LRRK2 is a potential therapeutic target. In addition, LRRK2 inhibitors might provide valuable tools to understand the pathophysiological and physiological roles of LRRK2 as well as the etiology of PD. We discuss here the potential and feasibility of targeting LRRK2 as a therapeutic strategy for PD.

4 Article Characterization of Parkinson's disease-related pathogenic TMEM230 mutants. 2018

Nam, Daleum / Kim, Hyejung / Choi, Dong-Joo / Bae, Yun-Hee / Lee, Byoung Dae / Son, Ilhong / Seol, Wongi. ·InAm Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunposi, Gyeonggido, Republic of Korea. · Department of Pharmacology, School of Medicine, Ajou University, Suwonsi, Gyeonggido, Republic of Korea. · Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, Republic of Korea. · Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea. · Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, Gunposi, Gyeonggido, Republic of Korea. ·Anim Cells Syst (Seoul) · Pubmed #30460091.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease. Although most PD cases are sporadic, 5-10% of them are hereditary and several pathogenic mutations in related genes have been identified. Mutations in

5 Article Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration. 2018

Jeong, Ga Ram / Jang, Eun-Hae / Bae, Jae Ryul / Jun, Soyoung / Kang, Ho Chul / Park, Chi-Hu / Shin, Joo-Ho / Yamamoto, Yukio / Tanaka-Yamamoto, Keiko / Dawson, Valina L / Dawson, Ted M / Hur, Eun-Mi / Lee, Byoung Dae. ·Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, South Korea. · Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, South Korea. · Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, South Korea. · Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea. · Department of Physiology, Ajou University School of Medicine, Suwon, South Korea. · HuGex Co. Ltd., Incheon, South Korea. · Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Single Cell Network Research Center, SungKyunKwan University School of Medicine, Suwon, South Korea. · Center for Functional Connectomics, KIST, Seoul, South Korea. · Neurodegeneration and Stem Cell Program, Institute for Cell Engineering and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, USA. · Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, USA. · Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, USA. · Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, South Korea. ehur@kist.re.kr. · Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, KIST, Seoul, South Korea. ehur@kist.re.kr. · Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea. ehur@kist.re.kr. · Department of Neuroscience, Graduate School, Kyung Hee University, Seoul, South Korea. bdaelee@khu.ac.kr. · Department of Physiology, School of Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea. bdaelee@khu.ac.kr. ·Mol Neurodegener · Pubmed #29439717.

ABSTRACT: BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo. METHODS: In vitro LRRK2 kinase assay with forty-five purified human Rab GTPases was performed to identify Rab family proteins as substrates of LRRK2. We identified the phosphorylation site by tandem mass-spectrometry and confirmed it by assessing phosphorylation in the in vitro LRRK2 kinase assay and in cells. Effects of Rab phosphorylation on neurodegeneration were examined in primary cultures and in vivo by intracranial injection of adeno-associated viral vectors (AAV) expressing wild-type or phosphomutants of Rab35. RESULTS: Our screening revealed that LRRK2 phosphorylated several Rab GTPases at a conserved threonine residue in the switch II region, and by using the kinase-inactive LRRK2-D1994A and the pathogenic LRRK2-G2019S along with Rab proteins in which the LRRK2 site was mutated, we verified that a subset of Rab proteins, including Rab35, were authentic substrates of LRRK2 both in vitro and in cells. We also showed that phosphorylation of Rab regulated GDP/GTP-binding property in cells. Moreover, in primary cortical neurons, mutation of the LRRK2 site in several Rabs caused neurotoxicity, which was most severely induced by phosphomutants of Rab35. Furthermore, intracranial injection of the AAV-Rab35 -T72A or AAV-Rab35-T72D into the substantia nigra substantially induced degeneration of dopaminergic neurons in vivo. CONCLUSIONS: Here we show that a subset of Rab GTPases are authentic substrates of LRRK2 both in vitro and in cells. We also provide evidence that dysregulation of Rab phosphorylation in the LRRK2 site induces neurotoxicity in primary neurons and degeneration of dopaminergic neurons in vivo. Our study suggests that Rab GTPases might mediate LRRK2 toxicity in the progression of PD.

6 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.

7 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.

8 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

9 Article TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson's disease via CNTF. 2015

Nam, Jin H / Park, Eun S / Won, So-Yoon / Lee, Yu A / Kim, Kyoung I / Jeong, Jae Y / Baek, Jeong Y / Cho, Eun J / Jin, Minyoung / Chung, Young C / Lee, Byoung D / Kim, Sung Hyun / Kim, Eung-Gook / Byun, Kyunghee / Lee, Bonghee / Woo, Dong Ho / Lee, C Justin / Kim, Sang R / Bok, Eugene / Kim, Yoon-Seong / Ahn, Tae-Beom / Ko, Hyuk Wan / Brahmachari, Saurav / Pletinkova, Olga / Troconso, Juan C / Dawson, Valina L / Dawson, Ted M / Jin, Byung K. ·1 Department of Biochemistry and Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Centre, School of Medicine Kyung Hee University, Seoul 130-701, Korea. · 2 Department of Biochemistry and Signaling Disorder Research Centre, College of Medicine, Chungbuk National University, Cheongju 361-763, Korea. · 3 Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon 406-840, Korea. · 4 Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul 130-701, Korea. · 5 School of Life Sciences, BK21 Plus KNU Creative Bio Research Group, Kyungpook National University, Daegu 702-701, Korea. · 1 Department of Biochemistry and Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Centre, School of Medicine Kyung Hee University, Seoul 130-701, Korea 6 Burnett School of Biomedical Sciences, College of Medicine University of Central Florida, FL 32827, USA. · 6 Burnett School of Biomedical Sciences, College of Medicine University of Central Florida, FL 32827, USA. · 7 Department of Neurology, School of Medicine, Kyung Hee University, Seoul 130-701, Korea. · 8 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 10 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. · 11 Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. · 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 11 Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. · 8 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 12 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 13 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 14 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · 8 Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 9 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 10 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 12 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA 14 Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA 15 Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. · 1 Department of Biochemistry and Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Centre, School of Medicine Kyung Hee University, Seoul 130-701, Korea bkjin@khu.ac.kr. ·Brain · Pubmed #26490328.

ABSTRACT: Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus α-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease.

10 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.

11 Article Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. 2014

Martin, Ian / Kim, Jungwoo Wren / Lee, Byoung Dae / Kang, Ho Chul / Xu, Jin-Chong / Jia, Hao / Stankowski, Jeannette / Kim, Min-Sik / Zhong, Jun / Kumar, Manoj / Andrabi, Shaida A / Xiong, Yulan / Dickson, Dennis W / Wszolek, Zbigniew K / Pandey, Akhilesh / Dawson, Ted M / Dawson, Valina L. ·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, 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; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, 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; 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, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Ajou University School of Medicine, Suwon 443-749, 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. · Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. · Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA. · Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, 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; 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, USA. Electronic address: tdawson@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; 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; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: vdawson@jhmi.edu. ·Cell · Pubmed #24725412.

ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.

12 Article Measuring the activity of leucine-rich repeat kinase 2: a kinase involved in Parkinson's disease. 2012

Lee, Byoung Dae / Li, Xiaojie / Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Methods Mol Biol · Pubmed #21960214.

ABSTRACT: Mutations in the LRRK2 (Leucine-Rich Repeat Kinase 2) gene are the most common cause of autosomal dominant Parkinson's disease. LRRK2 has multiple functional domains including a kinase domain. The kinase activity of LRRK2 is implicated in the pathogenesis of Parkinson's disease. Developing an assay to understand the mechanisms of LRRK2 kinase activity is important for the development of pharmacologic and therapeutic applications. Here, we describe how to measure in vitro LRRK2 kinase activity and its inhibition.

13 Article Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models. 2011

Liu, Zhaohui / Hamamichi, Shusei / Lee, Byoung Dae / Yang, Dejun / Ray, Arpita / Caldwell, Guy A / Caldwell, Kim A / Dawson, Ted M / Smith, Wanli W / Dawson, Valina L. ·Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA. ·Hum Mol Genet · Pubmed #21768216.

ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) have been identified as a genetic cause of familial Parkinson's disease (PD) and have also been found in the more common sporadic form of PD, thus positioning LRRK2 as important in the pathogenesis of PD. Biochemical studies of the disease-causing mutants of LRRK2 implicates an enhancement of kinase activity as the basis of neuronal toxicity and thus possibly the pathogenesis of PD due to LRRK2 mutations. Previously, a chemical library screen identified inhibitors of LRRK2 kinase activity. Here, two of these inhibitors, GW5074 and sorafenib, are shown to protect against G2019S LRRK2-induced neurodegeneration in vivo in Caenorhabditis elegans and in Drosophila. These findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of LRRK2 activity can have a disease-modifying effect. This suggests that inhibition of LRRK2 holds promise as a treatment for PD.

14 Article Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. 2010

Lee, Byoung Dae / Shin, Joo-Ho / VanKampen, Jackalina / Petrucelli, Leonard / West, Andrew B / Ko, Han Seok / Lee, Yun-Il / Maguire-Zeiss, Kathleen A / Bowers, William J / Federoff, Howard J / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration Program, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Nat Med · Pubmed #20729864.

ABSTRACT: Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease.

15 Minor LRRK2 and membrane trafficking: nexus of Parkinson's disease. 2019

Hur, Eun-Mi / Jang, Eun-Hae / Jeong, Ga Ram / Lee, Byoung Dae. ·Department of Neuroscience, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul 08826, Korea. · Department of Neuroscience, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul 08826; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea. · Department of Neuroscience, Kyung Hee University, Seoul 02447, Korea. · Department of Neuroscience, Kyung Hee University, Seoul 02447; Department of Physiology, Kyung Hee University School of Medicine, Seoul 02447, Korea. ·BMB Rep · Pubmed #31383252.

ABSTRACT: Recent evidence from genetics, animal model systems and biochemical studies suggests that defects in membrane trafficking play an important part in the pathophysiology of Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) constitute the most frequent genetic cause of both familial and sporadic PD, and LRRK2 has been suggested as a druggable target for PD. Although the precise physiological function of LRRK2 remains largely unknown, mounting evidence suggests that LRRK2 controls membrane trafficking by interacting with key regulators of the endosomal-lysosomal pathway and synaptic recycling. In this review, we discuss the genetic, biochemical and functional links between LRRK2 and membrane trafficking. Understanding the mechanism by which LRRK2 influences such processes may contribute to the development of disease-modifying therapies for PD. [BMB Reports 2019; 52(9): 533-539].

16 Minor Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. 2011

Ramsden, Nigel / Perrin, Jessica / Ren, Zhao / Lee, Byoung Dae / Zinn, Nico / Dawson, Valina L / Tam, Danny / Bova, Michael / Lang, Manja / Drewes, Gerard / Bantscheff, Marcus / Bard, Frederique / Dawson, Ted M / Hopf, Carsten. · ·ACS Chem Biol · Pubmed #21812418.

ABSTRACT: Leucine-rich repeat kinase-2 (LRRK2) mutations are the most important cause of familial Parkinson's disease, and non-selective inhibitors are protective in rodent disease models. Because of their poor potency and selectivity, the neuroprotective mechanism of these tool compounds has remained elusive so far, and it is still unknown whether selective LRRK2 inhibition can attenuate mutant LRRK2-dependent toxicity in human neurons. Here, we employ a chemoproteomics strategy to identify potent, selective, and metabolically stable LRRK2 inhibitors. We demonstrate that CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency. These precise chemical probes further validate this emerging therapeutic strategy. They will enable more detailed studies of LRRK2-dependent signaling and pathogenesis and accelerate drug discovery.