title: Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease.
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.
authors.affiliation: MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester, UK.
authors.forename: Joern R
authors.initials: JR
authors.lastname: Steinert
authors.forename: Susanna
authors.initials: S
authors.lastname: Campesan
authors.forename: Paul
authors.initials: P
authors.lastname: Richards
authors.forename: Charalambos P
authors.initials: CP
authors.lastname: Kyriacou
authors.forename: Ian D
authors.initials: ID
authors.lastname: Forsythe
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D055724:Electrophysiological Phenomena; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism; D007814:Larva / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009410:Nerve Degeneration; D009469:Neuromuscular Junction / Q000502:physiology*; D013569:Synapses / Q000502:physiology; D055366:Synaptic Potentials; D009435:Synaptic Transmission; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D029721:Drosophila Proteins; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D020691:rab GTP-Binding Proteins; C542005:Htt protein, Drosophila; C559123:Rab11 protein, Drosophila; D000099193:rab11 GTP-Binding Proteins