Polyglutamine （polyQ） diseases are a family of neurodegenerative disorders including Huntington’s disease, spinobulbar muscular atrophy,dentatorubral-pallidoluysian atrophy and several spinocerebellar ataxias.polyQ...Polyglutamine （polyQ） diseases are a family of neurodegenerative disorders including Huntington’s disease, spinobulbar muscular atrophy,dentatorubral-pallidoluysian atrophy and several spinocerebellar ataxias.polyQ diseases are caused by abnormal expansion of CAG repeats in certain genes.The expanded CAG repeats are then translated into a series of abnormally expanded polyQ tracts.Such polyQ tracts may induce misfolding of the disease-causing proteins.The present review mainly focuses on the common characteristics of the pathogenesis of these polyQ diseases,including conformational transition of proteins and its influence on the function of these proteins,the correlation between decreased ability of proteoly-sis and late-onset polyQ diseases,and the relationship between wide expression of disease-causing proteins and selective neuronal death.展开更多
Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene produc...Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene product, ataxin-3 （AT3）. This disease is characterized by the formation of intraneuronal inclusions, but the mechanism underlying their formation is still poorly understood. The present study is to explore the relationship between wild type （WT） AT3 and polyQ expanded AT3. Methods Mouse neuroblastoma （N2a） cells or HEK293 cells were co-transfected with WTAT3 and different truncated forms of expanded AT3. The expressions of WT AT3 and the truncated forms of expanded AT3 were detected by Western blotting, and observed by an inverted fluorescent microscope. The interactions between AT3 and different truncated forms of expanded AT3 were detected by immunoprecipitation and GST pull-down assays. Results Using fluorescent microscope, we observed that the truncated forms of expanded AT3 aggregate in transfected cells, and the full-length WT AT3 is recruited onto the aggregates. However, no aggregates were observed in cells transfected with the truncated forms of WT AT3. Immunoprecipitation and GST pull-down analyses indicate that WT AT3 interacts with the truncated AT3 in a polyQ length-dependent manner. Conclusion WT AT3 deposits in the aggregation that was formed by polyQ expanded AT3, which suggests that the formation of AT3 aggregation may affect the normal function of WT AT3 and increase polyQ protein toxicity in MJD.展开更多
基金supported by the grants from the National Natural Science Foundation of China(No.30600197)the Specialized Research Fund for the Doctoral Program of Higher Education of China(No.20050285017)
文摘Polyglutamine （polyQ） diseases are a family of neurodegenerative disorders including Huntington’s disease, spinobulbar muscular atrophy,dentatorubral-pallidoluysian atrophy and several spinocerebellar ataxias.polyQ diseases are caused by abnormal expansion of CAG repeats in certain genes.The expanded CAG repeats are then translated into a series of abnormally expanded polyQ tracts.Such polyQ tracts may induce misfolding of the disease-causing proteins.The present review mainly focuses on the common characteristics of the pathogenesis of these polyQ diseases,including conformational transition of proteins and its influence on the function of these proteins,the correlation between decreased ability of proteoly-sis and late-onset polyQ diseases,and the relationship between wide expression of disease-causing proteins and selective neuronal death.
基金the National Natural Sciences Foundation of China (No.30770664)a grant from Anhui Educational Committee(No. ZD2008008-2)
文摘Objective Machado-Joseph disease （MJD）, also known as spinocerebellar ataxia type 3 （SCA3）, is a dominant neurodegenerative disorder caused by an expansion of the polyglutamine （polyQ） tract in MJD-1 gene product, ataxin-3 （AT3）. This disease is characterized by the formation of intraneuronal inclusions, but the mechanism underlying their formation is still poorly understood. The present study is to explore the relationship between wild type （WT） AT3 and polyQ expanded AT3. Methods Mouse neuroblastoma （N2a） cells or HEK293 cells were co-transfected with WTAT3 and different truncated forms of expanded AT3. The expressions of WT AT3 and the truncated forms of expanded AT3 were detected by Western blotting, and observed by an inverted fluorescent microscope. The interactions between AT3 and different truncated forms of expanded AT3 were detected by immunoprecipitation and GST pull-down assays. Results Using fluorescent microscope, we observed that the truncated forms of expanded AT3 aggregate in transfected cells, and the full-length WT AT3 is recruited onto the aggregates. However, no aggregates were observed in cells transfected with the truncated forms of WT AT3. Immunoprecipitation and GST pull-down analyses indicate that WT AT3 interacts with the truncated AT3 in a polyQ length-dependent manner. Conclusion WT AT3 deposits in the aggregation that was formed by polyQ expanded AT3, which suggests that the formation of AT3 aggregation may affect the normal function of WT AT3 and increase polyQ protein toxicity in MJD.
