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

Neuron. 2008 Jan 10;57(1):27-40. doi: 10.1016/j.neuron.2007.11.025.

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 (128Qhtt(FL)) leads to behavioral, neurodegenerative, and electrophysiological phenotypes. These phenotypes are caused by a Ca2+-dependent increase in neurotransmitter release efficiency in 128Qhtt(FL) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Behavior, Animal
  • Calcium / metabolism
  • Cytoplasm / metabolism*
  • Disease Models, Animal
  • Drosophila
  • Eye / pathology
  • Eye / ultrastructure
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Huntingtin Protein
  • Huntington Disease
  • Larva
  • Microscopy, Electron, Scanning / methods
  • Mutation / genetics
  • Nerve Degeneration / pathology
  • Nerve Degeneration / prevention & control*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurotransmitter Agents / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Synaptic Transmission / physiology*
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • Nuclear Proteins
  • Green Fluorescent Proteins
  • Calcium