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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Steinert JR,Campesan S,Richards P,Kyriacou CP,Forsythe ID,Giorgini Fdoi
10.1093/hmg/dds117subject
Has Abstractpub_date
2012-07-01 00:00:00pages
2912-22issue
13eissn
0964-6906issn
1460-2083pii
dds117journal_volume
21pub_type
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