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Sequential activation of individual caspases, and of alterations in Bcl‐2 proapoptotic signals in a mouse model of Huntington's disease
Author(s) -
Zhang Yu,
Ona Victor O.,
Li Mingwei,
Drozda Martin,
DuboisDauphin Michel,
Przedborski Serge,
Ferrante Robert J.,
Friedlander Robert M.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02105.x
Subject(s) - huntington's disease , caspase , genetically modified mouse , neurodegeneration , apoptosis , bcl 2 family , transgene , biology , programmed cell death , huntingtin , disease , neuroscience , microbiology and biotechnology , huntingtin protein , cancer research , genetics , medicine , pathology , gene
Caspases play an important role in neurodegeneration in Huntington's disease (HD). Members of the Bcl‐2 family are critical modulators of terminal cell death pathways. However, alterations of Bcl‐2 family members and their functional role in an in vivo model of HD have not been documented. With the goal of gaining mechanistic insight, we used a transgenic mouse model of HD (R6/2) to investigate the chronology of caspase activation and functional alterations in members of the Bcl‐2 family. In R6/2 mice caspase activation precedes proapoptotic changes in Bcl‐2 family members. Of the caspases that we screened, caspase‐1‐like activation was the first to be detected in the disease process (7 weeks). Proapoptotic changes in members of the Bcl‐2 family were first detected at 9 weeks. To demonstrate a potential functional/therapeutic role of Bcl‐2 in HD, we crossed R6/2 mice with mice overexpressing Bcl‐2 in neurons. Transgenic expression of Bcl‐2 in R6/2 mice resulted in slight prolonged survival. Understanding the chronology of apoptotic events provides important information for appropriate therapeutic targeting in this devastating and untreatable disease.