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Polyglutamine aggregates stimulate ER stress and trigger apoptosis by activating BH-3 only protein Bim

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Date Issued:
2008
Summary:
Huntington's disease (HD) is an inherited neurological disorder characterized by a selective loss of neurons in the striatum and cortex leading to involuntary movement, dementia and eventually cell death. HD is caused by an expanded polyglutamine (PolyQ) repeat in Huntingtin (Htt) protein. It is well known that misfolded mutant Htt could form intracellular aggregates, trigger ER stress and ultimately lead to apoptosis. However, the molecular link between ER stress and apoptosis in mitochondria is poorly understood. In the present study, we identified Bim (Bcl-2 interacting mediator of cell death) as the essential protein. We first established a cellular model of HD by over expressing the Nterminus of wild type and mutant Htt into HEK293 cell lines. We showed that the accumulation and aggregation of misfolded mutant Htt protein triggers ER stress and apoptosis. The Bim protein expression level was greatly increased in mutant Htt transfected cells and this increase was partially due to up-regulation of Bim mRNA as analyzed using quantitative RT-PCR. We further showed that Bim phosphorylation also played an important role in regulating Bim expression. Moreover, up-regulation of Bim facilitates the translocation of Bax to mitochondrial membrane, which lead to cytochrome c release and apoptosis. We also silenced Bim using siRNA to further investigate the essential role of Bim in mutant Htt induced ER stress and apoptosis. Identifying the Bim pathway that is altered in response to the mutant Htt protein is important for understanding the cellular processes impacted by the disease.
Title: Polyglutamine aggregates stimulate ER stress and trigger apoptosis by activating BH-3 only protein Bim.
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Name(s): Bhagavatula, Nithya
Wei, Jianning, Thesis advisor
Florida Atlantic University, Degree grantor
Type of Resource: text
Genre: Electronic Thesis Or Dissertation
Date Created: 2008
Date Issued: 2008
Publisher: Florida Atlantic University
Place of Publication: Boca Raton, Fla.
Physical Form: application/pdf
Extent: 53 p.
Language(s): English
Summary: Huntington's disease (HD) is an inherited neurological disorder characterized by a selective loss of neurons in the striatum and cortex leading to involuntary movement, dementia and eventually cell death. HD is caused by an expanded polyglutamine (PolyQ) repeat in Huntingtin (Htt) protein. It is well known that misfolded mutant Htt could form intracellular aggregates, trigger ER stress and ultimately lead to apoptosis. However, the molecular link between ER stress and apoptosis in mitochondria is poorly understood. In the present study, we identified Bim (Bcl-2 interacting mediator of cell death) as the essential protein. We first established a cellular model of HD by over expressing the Nterminus of wild type and mutant Htt into HEK293 cell lines. We showed that the accumulation and aggregation of misfolded mutant Htt protein triggers ER stress and apoptosis. The Bim protein expression level was greatly increased in mutant Htt transfected cells and this increase was partially due to up-regulation of Bim mRNA as analyzed using quantitative RT-PCR. We further showed that Bim phosphorylation also played an important role in regulating Bim expression. Moreover, up-regulation of Bim facilitates the translocation of Bax to mitochondrial membrane, which lead to cytochrome c release and apoptosis. We also silenced Bim using siRNA to further investigate the essential role of Bim in mutant Htt induced ER stress and apoptosis. Identifying the Bim pathway that is altered in response to the mutant Htt protein is important for understanding the cellular processes impacted by the disease.
Identifier: FA00000726 (IID)
Collection: FAU Electronic Theses and Dissertations Collection
Note(s): Includes bibliography.
Dissertation (Ph.D.)--Florida Atlantic University, 2008.
Charles E. Schmidt College of Medicine
Subject(s): Nervous system--Degeneration--Molecular aspects
Apoptosis
Cellular signal transduction
Huntington's disease--Genetic aspects
Huntington's disease--Pathophysiology
Held by: Florida Atlantic University Libraries
Persistent Link to This Record: http://purl.flvc.org/fau/fd/FA00000726
Sublocation: Digital Library
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Host Institution: FAU
Is Part of Series: Florida Atlantic University Digital Library Collections.