[논문]Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease

Heo, Jun Young; Nam, Min-Ho; Yoon, Hyung Ho; Kim, Jeongyeon; Hwang, Yu Jin; Won, Woojin; Woo, Dong Ho; Lee, Ji Ae; Park, Hyun-Jung; Jo, Seonmi; Lee, Min Joung; Kim, Sunpil; Shim, Jeong-Eun; Jang, Dong-Pyo; Kim, Kyoung I.; Huh, Sue H.; Jeong, Jae Y.; Kowall, Neil W.; Lee, Junghee; Im, Hyeonjoo; Park, Jong Hyun; Jang, Bo Ko; Park, Ki Duk; Lee, Hyunjoo J.; Shin, Hyogeun; Cho, Il-Joo; Hwang, Eun Mi; Kim, YoungSoo; Kim, Hye Yun; Oh, Soo-Jin; Lee, Seung Eun; Paek, Sun Ha; Yoon, Jong Hyuk; Jin, Byung K.; Kweon, Gi Ryang; Shim, Insop; Hwang, Onyou; Ryu, Hoon; Jeon, Sang Ryong; Lee, C. Justin

doi:10.1016/j.cub.2019.11.079

[해외논문] Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease 원문보기

Current biology : CB, v.30 no.2, 2020년, pp.276 - 291.e9

Heo, Jun Young (Center for Neuroscience, Korea Institute of Science and Technology (KIST)) , Nam, Min-Ho (Center for Neuroscience, Korea Institute of Science and Technology (KIST)) , Yoon, Hyung Ho (Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine) , Kim, Jeongyeon (Center for Neuroscience, Korea Institute of Science and Technology (KIST)) , Hwang, Yu Jin (Center for Neuro-Medicine, Brain Science Institute, KIST) , Won, Woojin (Center for Neuroscience, Korea Institute of Science and Technology (KIST)) , Woo, Dong Ho (Center for Neuroscience, Korea Institute of Science and Technology (KIST)) , Lee, Ji Ae (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine) , Park, Hyun-Jung (Department of Science in Korean Medicine, Graduate School, Kyung Hee University) , Jo, Seonmi (Center for Neuroscience, Korea Institute of Science and Technol) , Lee, Min Joung , Kim, Sunpil , Shim, Jeong-Eun , Jang, Dong-Pyo , Kim, Kyoung I. , Huh, Sue H. , Jeong, Jae Y. , Kowall, Neil W. , Lee, Junghee , Im, Hyeonjoo , Park, Jong Hyun , Jang, Bo Ko , Park, Ki Duk , Lee, Hyunjoo J. , Shin, Hyogeun , Cho, Il-Joo , Hwang, Eun Mi , Kim, YoungSoo , Kim, Hye Yun , Oh, Soo-Jin , Lee, Seung Eun , Paek, Sun Ha , Yoon, Jong Hyuk , Jin, Byung K. , Kweon, Gi Ryang , Shim, Insop , Hwang, Onyou , Ryu, Hoon , Jeon, Sang Ryong , Lee, C. Justin

Abstract ▼ AI-Helper

Summary 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. Highlights Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation Graphical Abstract [DISPLAY OMISSION]

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