Year: 2001
Type: dissertation
Abstract: Huntington's Disease is a neurodegenerative disease that leads to progressive cell death of a select set of neurons. It is caused by the expansion of a stretch of glutamines in the N-terminus of the Huntingtin (Htt) protein. This gain-of-function event results in increased apoptosis of striatal neurons. Wild-type (wt) Htt is an ubiquitously expressed protein whose function remains largely unknown. Mice with a targeted disruption of the Htt gene die early in utero. In this work, the question of the function of wtHtt and the apoptotic pathways engaged by the poly-Q expanded mutant (mu) Htt is addressed. Results show that wtHtt is an anti-apoptotic protein that protects striatal cell lines from various apoptotic stimuli. Htt acts downstream of mitochondrial Cytochrome c release and interacts with the catalytic domain of Caspase-9. This interaction leads to decreased Cytochrome c-dependent cleavage of pro- Caspase-9 and decreased catalytic activity, probably through inhibition of proper apoptosome formation. The results also show that muHtt does retain some of the function of the wt protein, most markedly interaction with Caspase-9. In addition, muHtt induces apoptosis in striatal cell lines by a mechanism that involves Caspase-3 activation. Most importantly, pro-apoptotic activity of muHtt is also observed in C. elegans.
Author: Bauer, Johannes H.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1762510399