Document Detail


BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin.
MedLine Citation:
PMID:  20497470     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Huntington's disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the N-terminus of the huntingtin protein. It is characterized by a selective loss of medium spiny neurons in the striatum. It has been suggested that impaired proteasome function and endoplasmic reticulum (ER) stress play important roles in mutant huntingtin (mHtt)-induced cell death. However, the molecular link involved is poorly understood. In the present study, we identified the essential role of the extra long form of Bim (Bcl-2 interacting mediator of cell death), BimEL, in mHtt-induced cell death. BimEL protein expression level was significantly increased in cell lines expressing the N-terminus of mHtt and in a mouse model of HD. Although quantitative RT-PCR analysis indicated that BimEL mRNA was increased in cells expressing mHtt, we provided evidence showing that, at the post-translational level, phosphorylation of BimEL played a more important role in regulating BimEL expression. Up-regulation of BimEL facilitated the translocation of Bax to the mitochondrial membrane, which further led to cytochrome c release and cell death. On the other hand, knocking down BimEL expression prevented mHtt-induced cell death. Taken together, these findings suggest that BimEL is a key element in regulating mHtt-induced cell death. A model depicting the role of BimEL in linking mHtt-induced ER stress and proteasome dysfunction to cell death is proposed.
Authors:
Rebecca Leon; Nithya Bhagavatula; Onome Ulukpo; Mark McCollum; Jianning Wei
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-24
Journal Detail:
Title:  The European journal of neuroscience     Volume:  31     ISSN:  1460-9568     ISO Abbreviation:  Eur. J. Neurosci.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-07-07     Completed Date:  2010-10-25     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8918110     Medline TA:  Eur J Neurosci     Country:  France    
Other Details:
Languages:  eng     Pagination:  1915-25     Citation Subset:  IM    
Affiliation:
Department of Basic Science, Charles E. Schmidt College of Biomedical Science, Florida Atlantic University, Boca Raton, FL 33431, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis Regulatory Proteins / genetics,  metabolism*
Cell Death / physiology*
Cell Line
Disease Models, Animal
Endoplasmic Reticulum / metabolism
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
Huntington Disease / physiopathology*
JNK Mitogen-Activated Protein Kinases / metabolism
Membrane Proteins / genetics,  metabolism*
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Mitochondria / metabolism
Nerve Tissue Proteins* / genetics,  metabolism
Nuclear Proteins* / genetics,  metabolism
Proteasome Endopeptidase Complex / physiology*
Proto-Oncogene Proteins / genetics,  metabolism*
RNA, Small Interfering / genetics,  metabolism
bcl-2-Associated X Protein / metabolism
Grant Support
ID/Acronym/Agency:
R15 NS066339-01/NS/NINDS NIH HHS; R15NS066339/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Bcl-2-like protein 11; 0/Huntington protein, mouse; 0/Membrane Proteins; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 0/bcl-2-Associated X Protein; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

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