Suppression of Neurodegeneration and Increased Neurotransmission Caused by Expanded Full-Length Huntingtin Accumulating in the Cytoplasm

Eliana Romero, Guang Ho Cha, Patrik Verstreken, Cindy V. Ly, Robert E. Hughes, Hugo J. Bellen, Juan Botas

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

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 (128QhttFL) 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.

Original languageEnglish
Pages (from-to)27-40
Number of pages14
JournalNeuron
Volume57
Issue number1
DOIs
StatePublished - Jan 10 2008
Externally publishedYes

Keywords

  • HUMDISEASE
  • MOLNEURO

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