Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress.

Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress. Research Abstract Details 

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Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress. Abstract Text:

Takahiro Seki,Hideyuki Takahashi,Naoko Adachi,Nana Abe,Takayuki Shimahara,Naoaki Saito,Norio Sakai,Takahiro Seki,Hideyuki Takahashi,Naoko Adachi,Nana Abe,Takayuki Shimahara,Naoaki Saito,Norio Sakai,

Several causal missense mutations in protein kinase Cgamma (gammaPKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that mutant gammaPKC found in SCA14 is susceptible to two types of aggregation, cytoplasmic dot-like and perinuclear massive aggregation, and causes cell death in Chinese hamster ovary cells. Long-term time-lapse imaging revealed that firstly accumulated dot-like aggregation of mutant gammaPKC-green fluorescent protein (GFP) gradually formed perinuclear massive aggregations, followed by cell death. However, it remains unclear how aggregate formation of mutant gammaPKC causes cell death. In the present study, we examined whether these mutant aggregations affect the ubiquitin-proteasome system (UPS) and endoplasmic reticular (ER) stress. Two mutant gammaPKC-GFPs (S119P and G128D) were strongly ubiquitinated, and dot-like aggregations of these mutants were ubiquitin-positive and colocalized with proteasome 20S. Furthermore, proteasome activity in cells with aggregates, especially massive ones, was significantly decreased. Aggregate formation of mutant gammaPKC-GFP induced phosphorylation of PERK (PKR-like ER kinase) and nuclear expression of CHOP (C/EBP homologous protein), hallmarks of ER stress and subsequently activated caspase-3. These results indicate that aggregate formation of mutant gammaPKC found in SCA14 impairs UPS and induces ER stress, leading to apoptotic cell death.

Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress. Publishing Authors By Initials

T Seki,H Takahashi,N Adachi,N Abe,T Shimahara,N Saito,N Sakai,T Seki,H Takahashi,N Adachi,N Abe,T Shimahara,N Saito,N Sakai,

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Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The European journal of neuroscience

VOLUME: 26

Page Numbers: 3126-40

Journal Abbreviation: Eur. J. Neurosci.

ISSN: 0953-816X

DAY: 14

MONTH: 11

YEAR: 2007

Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress. Information

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LANGUAGE: eng

NlmUniqueID: 8918110

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Grant and Affiliation Information for Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress.

AFFILIATION: Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.

Country: France

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MEDLINETA: Eur J Neurosci

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