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Parkinson Disease: HELP
Articles by Seung Pil Yun
Based on 12 articles published since 2010
(Why 12 articles?)
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Between 2010 and 2020, Seung Pil Yun wrote the following 12 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 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.

2 Article Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson's disease. 2018

Kam, Tae-In / Mao, Xiaobo / Park, Hyejin / Chou, Shih-Ching / Karuppagounder, Senthilkumar S / Umanah, George Essien / Yun, Seung Pil / Brahmachari, Saurav / Panicker, Nikhil / Chen, Rong / Andrabi, Shaida A / Qi, Chen / Poirier, Guy G / Pletnikova, Olga / Troncoso, Juan C / Bekris, Lynn M / Leverenz, James B / Pantelyat, Alexander / Ko, Han Seok / Rosenthal, Liana S / 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 70130-2685, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. · Centre de recherche du CHU de Québec-Pavillon CHUL, Faculté de Médecine, Université Laval, Québec G1V 4G2, Canada. · Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Lerner Research Institute, Genomic Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. · Lou Ruvo Center for Brain Health, Neurological Institute, and Department of Neurology, Cleveland Clinic, Cleveland, OH 44195, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu vdawson1@jhmi.edu. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ·Science · Pubmed #30385548.

ABSTRACT: The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologic α-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.

3 Article Graphene quantum dots prevent α-synucleinopathy in Parkinson's disease. 2018

Kim, Donghoon / Yoo, Je Min / Hwang, Heehong / Lee, Junghee / Lee, Su Hyun / Yun, Seung Pil / Park, Myung Jin / Lee, MinJun / Choi, Seulah / Kwon, Sang Ho / Lee, Saebom / Kwon, Seung-Hwan / Kim, Sangjune / Park, Yong Joo / Kinoshita, Misaki / Lee, Young-Ho / Shin, Seokmin / Paik, Seung R / Lee, Sung Joong / Lee, Seulki / Hong, Byung Hee / 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. · Department of Chemistry, College of Natural Science, Seoul National University, Seoul, Republic of Korea. · Department of Neuroscience and Physiology, Interdisciplinary Program in Neuroscience, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Republic of Korea. · Inter-University Semiconductor Research Centre, Seoul National University, Seoul, Republic of Korea. · 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. · Institute for Protein Research, Osaka University, Yamadaoka, Osaka, Japan. · School of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul, Republic of Korea. · The Centre for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Chemistry, College of Natural Science, Seoul National University, Seoul, Republic of Korea. byunghee@snu.ac.kr. · Inter-University Semiconductor Research Centre, Seoul National University, Seoul, Republic of Korea. byunghee@snu.ac.kr. · 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 Nanotechnol · Pubmed #29988049.

ABSTRACT: Though emerging evidence indicates that the pathogenesis of Parkinson's disease is strongly correlated to the accumulation

4 Article The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson's disease mouse model. 2018

Lee, Saebom / Kim, Sangjune / Park, Yong Joo / Yun, Seung Pil / Kwon, Seung-Hwan / Kim, Donghoon / Kim, Dong Yeon / Shin, Jae Soo / Cho, Dae Jin / Lee, Gong Yeal / Ju, Hyun Soo / Yun, Hyo Jung / Park, Jae Hong / Kim, Wonjoong Richard / Jung, Eun Ah / Lee, Seulki / Ko, Han Seok. ·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. · The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. · Central Research Institute, Il-Yang Pharmaceutical Co. Ltd., Yongin-si, Gyeonggi-do, Republic of Korea. · The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuraly, Inc., Germantown, MD 20876, USA. · Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA. ·Hum Mol Genet · Pubmed #29897434.

ABSTRACT: Accumulating evidence suggests that the non-receptor tyrosine kinase c-Abl plays an important role in the progression of Parkinson's disease (PD) and c-Abl inhibition could be neuroprotective in PD and related α-synucleinopathies. Nilotinib, a c-Abl inhibitor, has shown improved motor and cognitive symptoms in PD patients. However, issues concerning blood-brain barrier (BBB) penetration, lack of selectivity and safety still remain. Radotinib HCl is a selective Bcr-Abl kinase inhibitor that not only effectively access the brain, but also exhibits greater pharmacokinetic properties and safety profiles compared to Nilotinib and other c-Abl inhibitors. Here, we show the neuroprotective efficacy of Radotinib HCl, a brain penetrant c-Abl inhibitor, in a pre-clinical model of PD. Importantly, in vitro studies demonstrate that the treatment of Radotinib HCl protects the α-synuclein preformed fibrils (PFF)-induced neuronal toxicity, reduces the α-synuclein PFF-induced Lewy bodies (LB)/Lewy neurites (LN)-like pathology and inhibits the α-synuclein PFF-induced c-Abl activation in primary cortical neurons. Furthermore, administration of Radotinib HCl inhibits c-Abl activation and prevents dopaminergic neuron loss, neuroinflammation and behavioral deficits following α-synuclein PFF-induced toxicity in vivo. Taken together, our findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides an evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD and related α-synucleinopathies.

5 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

6 Article A novel extended form of alpha-synuclein 3'UTR in the human brain. 2018

Je, Goun / Guhathakurta, Subhrangshu / Yun, Seung Pil / Ko, Han Seok / Kim, Yoon-Seong. ·Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA. · 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. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. · Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA. Yoon-Seong.Kim@ucf.edu. · College of Medicine, Kyung-Hee University, Seoul, South Korea. Yoon-Seong.Kim@ucf.edu. ·Mol Brain · Pubmed #29801501.

ABSTRACT: Alpha-synuclein (α-SYN) is one of the key contributors in Parkinson's disease (PD) pathogenesis. Despite the fact that increased α-SYN levels are considered one of the key contributors in developing PD, the molecular mechanisms underlying the regulation of α-SYN still needs to be elucidated. Since the 3' untranslated regions (3'UTRs) of messenger RNAs (mRNAs) have important roles in translation, localization, and stability of mRNAs through RNA binding proteins (RBPs) and microRNAs (miRNAs), it is important to identify the exact length of 3'UTRs of transcripts in order to understand the precise regulation of gene expression. Currently annotated human α-SYN mRNA has a relatively long 3'UTR (2529 nucleotides [nt]) with several isoforms. RNA-sequencing and epigenomics data have suggested, however, the possible existence of even longer transcripts which extend beyond the annotated α-SYN 3'UTR sequence. Here, we have discovered the novel extended form of α-SYN 3'UTR (3775 nt) in the substantia nigra of human postmortem brain samples, induced pluripotent stem cell (iPSC)-derived dopaminergic neurons, and other human neuronal cell lines. Interestingly, the longer variant reduced α-SYN translation. The extended α-SYN 3'UTR was significantly lower in iPSC-derived dopaminergic neurons from sporadic PD patients than controls. On the other hand, α-SYN protein levels were much higher in PD cases, showing the strong negative correlation with the extended 3'UTR. These suggest that dysregulation of the extended α-SYN 3'UTR might contribute to the pathogenesis of PD.

7 Article GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers. 2018

Kim, Sangjune / Yun, Seung Pil / Lee, Saebom / Umanah, George Essien / Bandaru, Veera Venkata Ratnam / Yin, Xiling / Rhee, Peter / Karuppagounder, Senthilkumar S / Kwon, Seung-Hwan / Lee, Hojae / Mao, Xiaobo / Kim, Donghoon / Pandey, Akhilesh / Lee, Gabsang / Dawson, Valina L / Dawson, Ted M / Ko, Han Seok. ·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. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130. · Mckusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Biological Chemistry, 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. · Department of Physiology, 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. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; hko3@jhmi.edu. · Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130. ·Proc Natl Acad Sci U S A · Pubmed #29311330.

ABSTRACT: Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of α-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of α-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of α-syn tetramers. Here, we show that accumulation of GSLs due to GBA1 deficiency decreases α-syn tetramers and related multimers and increases α-syn monomers in CRISPR-GBA1 knockout (KO) SH-SY5Y cells. Moreover, α-syn tetramers and related multimers are decreased in N370S

8 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.

9 Article Acacetin inhibits neuronal cell death induced by 6-hydroxydopamine in cellular Parkinson's disease model. 2017

Kim, Sang Min / Park, Yong Joo / Shin, Myoung-Sook / Kim, Ha-Ryong / Kim, Min Jae / Lee, Sang Hun / Yun, Seung Pil / Kwon, Seung-Hwan. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Baltimore, MD 21205, USA. · Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Natural Constituents Research Center, Korea Institute of Science and Technology Gangneung, Institute of Natural Products, 25451, Republic of Korea. · Department of Pharmaceutical Engineering, Dongshin University, Naju 58245 Republic of Korea. · Department of Biochemistry, Medical Science Research Institute, Soonchunhyang University College of Medicine, Cheonan, South Chungcheong 31151, Republic of Korea. Electronic address: jhlee0407@sch.ac.kr. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Baltimore, MD 21205, USA. Electronic address: syun12@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Baltimore, MD 21205, USA. Electronic address: skwon28@jhmi.edu. ·Bioorg Med Chem Lett · Pubmed #29089232.

ABSTRACT: Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound isolated from Flos Chrysanthemi Indici, chrysanthemum, safflower, and Calamintha and Linaria species has been shown to have anti-cancer activity, indicating its potential clinical value in cancer treatment. In this study, we sought to study the potentials of acacetin in preventing human dopaminergic neuronal death via inhibition of 6-hydroxydopamine (6-OHDA)-induced neuronal cell death in the SH-SY5Y cells. Our results suggest that acacetin was effective in preventing 6-OHDA-induced neuronal cell death through regulation of mitochondrial-mediated cascade apoptotic cell death. Pretreatment with acacetin significantly inhibited neurotoxicity and neuronal cell death through reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) dysfunction. Acacetin also markedly acted on key molecules in apoptotic cell death pathways and reduced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinases (PI3K)/Akt, and glycogen synthase kinase-3beta (GSK-3β). These results suggested that acacetin could inhibit 6-OHDA-induced neuronal cell death originating from ROS-mediated cascade apoptosis pathway. Thus, the results of our study suggest that acacetin is a potent therapeutic agent for PD progression.

10 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.

11 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.

12 Article Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. 2016

Mao, Xiaobo / Ou, Michael Tianhao / Karuppagounder, Senthilkumar S / Kam, Tae-In / Yin, Xiling / Xiong, Yulan / Ge, Preston / Umanah, George Essien / Brahmachari, Saurav / Shin, Joo-Ho / Kang, Ho Chul / Zhang, Jianmin / Xu, Jinchong / Chen, Rong / Park, Hyejin / Andrabi, Shaida A / Kang, Sung Ung / Gonçalves, Rafaella Araújo / Liang, Yu / Zhang, Shu / Qi, Chen / Lam, Sharon / Keiler, James A / Tyson, Joel / Kim, Donghoon / Panicker, Nikhil / Yun, Seung Pil / Workman, Creg J / Vignali, Dario A A / Dawson, Valina L / Ko, Han Seok / 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. · 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. · 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. Department of Physiology, Ajou University School of Medicine, Suwon 443-721, 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 Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. · 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. Johns Hopkins Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA. · Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. · Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, 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. 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. tdawson@jhmi.edu hko3@jhmi.edu vdawson1@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. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. tdawson@jhmi.edu hko3@jhmi.edu vdawson1@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. Johns Hopkins Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, 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. tdawson@jhmi.edu hko3@jhmi.edu vdawson1@jhmi.edu. ·Science · Pubmed #27708076.

ABSTRACT: Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.