Academic Journal
Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease‐associated ubiquitin C‐terminal hydrolase L1 and alters its structure and function
| العنوان: | Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease‐associated ubiquitin C‐terminal hydrolase L1 and alters its structure and function |
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| المؤلفون: | Contu, Viorica Raluca, Kotake, Yaichiro, Toyama, Takashi, Okuda, Katsuhiro, Miyara, Masatsugu, Sakamoto, Shuichiro, Samizo, Shigeyoshi, Sanoh, Seigo, Kumagai, Yoshito, Ohta, Shigeru |
| المساهمون: | JSPS Grant-in-Aid for Scientific Research, Grant-in-Aid for Challenging Exploratory Research |
| المصدر: | Journal of Neurochemistry ; volume 130, issue 6, page 826-838 ; ISSN 0022-3042 1471-4159 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2014 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | 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′ DHB n TIQ ) is an endogenous parkinsonism‐inducing dopamine derivative. Here, we investigated the interaction between 3′,4′ DHB n TIQ and UCH ‐L1 and its possible role in the pathogenesis of idiopathic PD . Our results indicate that 3′,4′ DHB n TIQ binds to UCH ‐L1 specifically at Cys152 in vitro . In addition, 3′,4′ DHB n TIQ treatment increased the amount of UCH ‐L1 in the insoluble fraction of SH ‐ SY 5Y cells and inhibited its hydrolase activity to 60%, reducing the level of ubiquitin in the soluble fraction of SH ‐ SY 5Y 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′ DHB n TIQ might play a key role in onset and progression of idiopathic PD . image 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1111/jnc.12762 |
| الاتاحة: | http://dx.doi.org/10.1111/jnc.12762 https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fjnc.12762 https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.12762 |
| Rights: | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: | edsbas.91CE471F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1111/jnc.12762 |
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