Date of Award
2008
Document Type
Dissertation
Publication Status
Version of Record
Submission Date
October 2026
Thesis/Dissertation Advisor [Chair]
Wei, Jianning
Abstract
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.
Extent
53 p.
Recommended Citation
Bhagavatula, Nithya, "Polyglutamine aggregates stimulate ER stress and trigger apoptosis by activating BH-3 only protein Bim" (2008). Electronic Theses and Dissertations 2000 - 2009. 1539.
https://digitalcommons.fau.edu/etd_general_5/1539
Identifier
FA00000726
Comments
Includes bibliography.|Dissertation (Ph.D.)--Florida Atlantic University, 2008.|Charles E. Schmidt College of Medicine|FAU Electronic Theses and Dissertations Collection|Includes bibliography.