Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease-associated ubiquitin C-terminal hydrolase L1 and alters its structure and function.
Parkinson's disease (PD) is a common neurodegenerative disease, but its pathogenesis remains elusive. A mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) is responsible for a form of genetic PD which strongly resembles the idiopathic PD. We previously showed that 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3',4'DHBnTIQ) is an endogenous parkinsonism-inducing dopamine derivative. Here, we investigated the interaction between 3',4'DHBnTIQ and UCH-L1 and its possible role in the pathogenesis of idiopathic PD. Our results indicate that 3',4'DHBnTIQ binds to UCH-L1 specifically at Cys152 in vitro. In addition, 3',4'DHBnTIQ treatment increased the amount of UCH-L1 in the insoluble fraction of SH-SY5Y cells and inhibited its hydrolase activity to 60%, reducing the level of ubiquitin in the soluble fraction of SH-SY5Y cells. Catechol-modified UCH-L1 as well as insoluble UCH-L1 were detected in the midbrain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated PD model mice. Structurally as well as functionally altered UCH-L1 have been detected in the brains of patients with idiopathic PD. We suggest that conjugation of UCH-L1 by neurotoxic endogenous compounds such as 3',4'DHBnTIQ might play a key role in onset and progression of idiopathic PD. We investigated the interaction between ubiquitin C-terminal hydrolase L1 (UCH-L1) and the brain endogenous parkinsonism inducer 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3',4'DHBnTIQ). Our results indicate that 3',4'DHBnTIQ binds to UCH-L1 specifically at cysteine 152 and induces its aggregation. 3',4'DHBnTIQ also inhibits the hydrolase activity of UCH-L1. Catechol-modified as well as insoluble UCH-L1 were detected in the midbrains of MPTP-treated Parkinson's disease (PD) model mice. Conjugation of UCH-L1 by neurotoxic endogenous compounds like 3',4'DHBnTIQ might play a key role in onset and progression of PD.
Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Viorica Raluca
VR
Contu
Yaichiro
Y
Kotake
Takashi
T
Toyama
Katsuhiro
K
Okuda
Masatsugu
M
Miyara
Shuichiro
S
Sakamoto
Shigeyoshi
S
Samizo
Seigo
S
Sanoh
Yoshito
Y
Kumagai
Shigeru
S
Ohta
D000818:Animals; D015153:Blotting, Western; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009498:Neurotoxins / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014213:Tretoquinol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000378:metabolism*
C110419:1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline; D002396:Catechols; D007202:Indicators and Reagents; D009498:Neurotoxins; D011994:Recombinant Proteins; C507533:Ubiquitin carboxyl-Terminal Hydrolase L-1, human; D043222:Ubiquitin Thiolesterase; D014213:Tretoquinol; C034221:catechol; D004298:Dopamine
UCH-L1; aggregation; covalent modification; endogenous dopamine derivative