RRC ID 58387
Author Heo JY, Nam MH, Yoon HH, Kim J, Hwang YJ, Won W, Woo DH, Lee JA, Park HJ, Jo S, Lee MJ, Kim S, Shim JE, Jang DP, Kim KI, Huh SH, Jeong JY, Kowall NW, Lee J, Im H, Park JH, Jang BK, Park KD, Lee HJ, Shin H, Cho IJ, Hwang EM, Kim Y, Kim HY, Oh SJ, Lee SE, Paek SH, Yoon JH, Jin BK, Kweon GR, Shim I, Hwang O, Ryu H, Jeon SR, Lee CJ.
Title Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease.
Journal Curr Biol
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.
Volume 30(2)
Pages 276-291.e9
Published 2020-1-20
DOI 10.1016/j.cub.2019.11.079
PII S0960-9822(19)31581-7
PMID 31928877
MeSH Aged Aged, 80 and over Animals Astrocytes / metabolism* Disease Models, Animal Dopaminergic Neurons / physiology* Down-Regulation Female Humans Immobility Response, Tonic / physiology Male Mice Mice, Inbred C57BL Mice, Inbred ICR Middle Aged Nerve Degeneration / physiopathology* Parkinson Disease / physiopathology* Parkinson Disease / therapy Rats Rats, Wistar Tyrosine 3-Monooxygenase / antagonists & inhibitors Tyrosine 3-Monooxygenase / metabolism* gamma-Aminobutyric Acid / biosynthesis
IF 9.601
Times Cited 1
Mice RBRC02095