期刊
NEURON
卷 57, 期 1, 页码 27-40出版社
CELL PRESS
DOI: 10.1016/j.neuron.2007.11.025
关键词
-
资金
- NINDS NIH HHS [F30 NS056520, R01 NS042179, NS42179, R01 NS042179-01S2, R56 NS042179] Funding Source: Medline
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of a translated CAG repeat in the N terminus of the huntingtin (htt) protein. Here we describe the generation and characterization of a full-length HD Drosophila model to reveal a previously unknown disease mechanism that occurs early in the course of pathogenesis, before expanded htt is imported into the nucleus in detectable amounts. We find that expanded full-length htt (128Qhtt(FL)) leads to behavioral, neurodegenerative, and electrophysiological phenotypes. These phenotypes are caused by a Ca2+-dependent increase in neurotransmitter release efficiency in 128QhttFL animals. Partial loss of function in synaptic transmission (syntaxin, Snap, Rop) and voltage-gated Ca2+ channel genes suppresses both the electrophysiological and the neurodegenerative phenotypes. Thus, our data indicate that increased neurotransmission is at the root of neuronal degeneration caused by expanded full-length htt during early stages of pathogenesis.
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