Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington's disease.
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.
Zhang
Yu
Y
Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ona
Victor O
VO
Li
Mingwei
M
Drozda
Martin
M
Dubois-Dauphin
Michel
M
Przedborski
Serge
S
Ferrante
Robert J
RJ
Friedlander
Robert M
RM
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases