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Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease-associated ubiquitin C-terminal hydrolase L1 and alters its structure and function.

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'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.
AuthorsViorica Raluca Contu, Yaichiro Kotake, Takashi Toyama, Katsuhiro Okuda, Masatsugu Miyara, Shuichiro Sakamoto, Shigeyoshi Samizo, Seigo Sanoh, Yoshito Kumagai, Shigeru Ohta
JournalJournal of neurochemistry (J Neurochem) Vol. 130 Issue 6 Pg. 826-38 (Sep 2014) ISSN: 1471-4159 [Electronic] England
PMID24832624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 International Society for Neurochemistry.
Chemical References
  • 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline
  • Catechols
  • Indicators and Reagents
  • Neurotoxins
  • Recombinant Proteins
  • Ubiquitin carboxyl-Terminal Hydrolase L-1, human
  • Ubiquitin Thiolesterase
  • Tretoquinol
  • catechol
  • Dopamine
Topics
  • Animals
  • Blotting, Western
  • Catechols (chemistry, pharmacology)
  • Cell Line, Tumor
  • Cell Survival
  • Dopamine (analogs & derivatives, metabolism)
  • Electrophoresis, Agar Gel
  • Escherichia coli (metabolism)
  • Humans
  • Indicators and Reagents
  • Mesencephalon (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Neurotoxins (metabolism)
  • Parkinson Disease (metabolism)
  • Protein Binding
  • Recombinant Proteins (chemistry, isolation & purification)
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Tretoquinol (analogs & derivatives, metabolism, pharmacology)
  • Ubiquitin Thiolesterase (chemistry, metabolism)

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