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- Title
Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease-associated ubiquitin C-terminal hydrolase L1 and alters its structure and function.
- Authors
Contu, Viorica Raluca; Kotake, Yaichiro; Toyama, Takashi; Okuda, Katsuhiro; Miyara, Masatsugu; Sakamoto, Shuichiro; Samizo, Shigeyoshi; Sanoh, Seigo; Kumagai, Yoshito; Ohta, Shigeru
- Abstract
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′ DHBn TIQ) is an endogenous parkinsonism-inducing dopamine derivative. Here, we investigated the interaction between 3′,4′ DHBn TIQ and UCH-L1 and its possible role in the pathogenesis of idiopathic PD. Our results indicate that 3′,4′ DHBn TIQ binds to UCH-L1 specifically at Cys152 in vitro. In addition, 3′,4′ DHBn TIQ 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′ DHBn TIQ might play a key role in onset and progression of idiopathic PD.
- Subjects
UBIQUITIN carboxy-terminal hydrolase; NEUROTOXIC agents; DOPAMINE agents; NEURODEGENERATION; CATECHOL
- Publication
Journal of Neurochemistry, 2014, Vol 130, Issue 6, p826
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.12762