Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease

Hum Mol Genet. 2012 Jul 1;21(13):2912-22. doi: 10.1093/hmg/dds117. Epub 2012 Mar 30.

Abstract

Synapse abnormalities in Huntington's disease (HD) patients can precede clinical diagnosis and neuron loss by decades. The polyglutamine expansion in the huntingtin (htt) protein that underlies this disorder leads to perturbations in many cellular pathways, including the disruption of Rab11-dependent endosomal recycling. Impairment of the small GTPase Rab11 leads to the defective formation of vesicles in HD models and may thus contribute to the early stages of the synaptic dysfunction in this disorder. Here, we employ transgenic Drosophila melanogaster models of HD to investigate anomalies at the synapse and the role of Rab11 in this pathology. We find that the expression of mutant htt in the larval neuromuscular junction decreases the presynaptic vesicle size, reduces quantal amplitudes and evoked synaptic transmission and alters larval crawling behaviour. Furthermore, these indicators of early synaptic dysfunction are reversed by the overexpression of Rab11. This work highlights a potential novel HD therapeutic strategy for early intervention, prior to neuronal loss and clinical manifestation of disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Electrophysiological Phenomena
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Larva / genetics
  • Microtubule-Associated Proteins / genetics
  • Nerve Degeneration
  • Neuromuscular Junction / physiology*
  • Synapses / physiology
  • Synaptic Potentials
  • Synaptic Transmission*
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Drosophila Proteins
  • Htt protein, Drosophila
  • Huntingtin Protein
  • Microtubule-Associated Proteins
  • Rab11 protein, Drosophila
  • rab GTP-Binding Proteins