한빛사논문
Jun Young Heo1,2,3,25, Min-Ho Nam1,4,25, Hyung Ho Yoon5,25, Jeongyeon Kim1,6,25, Yu Jin Hwang7,25, Woojin Won1,8, Dong Ho Woo1, Ji Ae Lee9, Hyun-Jung Park4, Seonmi Jo1,10,11, Min Joung Lee2,3, Sunpil Kim1,8, Jeong-Eun Shim12, Dong-Pyo Jang12, Kyoung I. Kim13, Sue H. Huh13, Jae Y. Jeong13, Neil W. Kowall14,15,16, Junghee Lee14,15,16, Hyeonjoo Im1,7, Jong Hyun Park17, Bo Ko Jang17, Ki Duk Park17, Hyunjoo J. Lee18, Hyogeun Shin18, Il-Joo Cho18, Eun Mi Hwang23, YoungSoo Kim7,19, Hye Yun Kim19, Soo-Jin Oh1,17, Seung Eun Lee24, Sun Ha Paek20, Jong Hyuk Yoon21, Byung K. Jin13, Gi Ryang Kweon2,3, Insop Shim4, Onyou Hwang9, Hoon Ryu1,7,14,15,16,*, Sang Ryong Jeon5,*, C. Justin Lee1,8,22,26,*
1 Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea
2 Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea
3 Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea
4 Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea
5 Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
6 Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu 41062, Korea
7 Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul 02792, Korea
8 KU-KIST Graduate School of Converging Science of Technology, Korea University, Seoul 02841, Korea
9 Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 05505, Korea
10 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
11 Department of Genetic Resources Research, National Marine Biodiversity Institute of Korea, Seocheon 33662, Korea
12 Department of Biomedical Engineering, Hanyang University, Seoul 04763, Korea
13 Department of Biochemistry & Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 02447, Korea
14 Boston University Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA 02118, USA
15 Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
16 VA Boston Healthcare System, Boston, MA 02132, USA
17 Convergence Research Center for Dementia, KIST, Seoul 02792, Korea
18 Center for BioMicrosystems, Brain Science Institute, KIST, Seoul 02792, Korea
19 Department of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, and Integrated Science and Engineering Division, Yonsei University, Incheon 21983, Korea
20 Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea
21 Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea
22 Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Korea
23 Center for Functional Connectomics, KIST, Seoul 02792, Korea
24 Virus Facility, Research Animal Resource Center, KIST, Seoul 02792, Korea
25 These authors contributed equally
26 Lead Contact
*Corresponding author : Hoon Ryu, Sang Ryong Jeon, C. Justin Lee
Abstract
Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
Keywords : astrocytes; DOPA decarboxylase; GABA; Parkinson’s disease; tonic inhibition; tyrosine hydroxylase; MAO-B; substantia nigra pars compacta
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