Document Detail

Hrd1 facilitates tau degradation and promotes neuron survival.
MedLine Citation:
PMID:  22280354     Owner:  NLM     Status:  In-Data-Review    
Intraneuronal accumulation of abnormal phosphorylated tau (p-tau) is a molecular pathology in many neurodegenerative tauopathies, including Alzheimer's disease (AD) and frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17). However, the underlying mechanism remains unclear. Here, we showed an inverse relationship between endoplasmic reticulum membrane ubiquitin ligase (E3) Hrd1 expression and p-tau accumulation in the hippocampal neurons of AD, and proposed that Hrd1 may be a negative regulator of p-tau. This notion was further supported by in vitro study demonstrating that Hrd1 interacted with tau and promoted the degradation of total tau and p-tau as well. The degradation of tau depended on its Hrd1 E3 activity. Knockdown of endogenous Hrd1 with siRNA stabilized tau levels. In addition, inhibition of proteasome maintained tau level and increased Hrd1-mediated tau ubiquitination, suggesting the proteasome was involved in tau/p-tau degradation. Over-expression of Hrd1 significantly alleviated tau cytotoxicity and promoted cell survival. These results indicated that Hrd1 functions as an E3 targeting tau or abnormal p-tau for proteasome degradation. The study provides an important insight into the molecular mechanisms of human tauopathies.
Y X Shen; A M Sun; S Fang; L J Feng; Q Li; H L Hou; C Liu; H P Wang; J L Shen; J Luo; J N Zhou
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Current molecular medicine     Volume:  12     ISSN:  1875-5666     ISO Abbreviation:  Curr. Mol. Med.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101093076     Medline TA:  Curr Mol Med     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  138-52     Citation Subset:  IM    
81 Meishan Rd., Anhui Medical University. P.O. Box 8, Hefei 230032, China.
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