期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 1, 页码 86-99出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu456
关键词
-
资金
- Canadian Institute of Health Research (CIHR) [MOP-106423, PCN-102993]
- Fonds de Recherche en Sante du Quebec (FRQS) [16205, 20048]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [354722]
- Alzheimer Society of Canada
- CHUQ
- Faculty of Medicine at Universite Laval
- International Organization of Glutaric Acidemia
- Bourse d'excellence du Centre Thematique de Recherche en Neurosciences
- Alzheimer Society of Canada Biomedical Doctoral award
- Alzheimer Society of Canada Biomedical Post-Doctoral award
- Norampac Doctoral Scholarship for Research on Alzheimer's disease
- National Research Career award from the FRQS
- CIHR New Investigator Salary Award
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% insymptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据