Live axonal transport disruption by mutant huntingtin fragments in Drosophila motor neuron axons

Abstract

Huntington's Disease is a neurodegenerative condition caused by a polyglutamine expansion in the
huntingtin (Htt) protein, which aggregates and also causes neuronal dysfunction. Pathogenic N-terminal htt
fragments perturb axonal transport in vitro. To determine whether this occurs in vivo and to elucidate how
transport is affected, we expressed htt exon 1 with either pathogenic (HttEx1Q93) or non-pathogenic (HttEx1Q20) polyglutamine tracts in Drosophila. We found that HttEx1Q93 expression causes axonal
accumulation of GFP-tagged fast axonal transport vesicles in vivo and leads to aggregates within larval motor
neuron axons. Time-lapse video microscopy, shows that vesicle velocity is unchanged in HttEx1Q93-axons
compared to HttEx1Q20-axons, but vesicle stalling occurs to a greater extent. Whilst HttEx1Q93 expression
did not affect locomotor behaviour, external heat stress unveiled a locomotion deficit in HttEx1Q93 larvae.
Therefore vesicle transport abnormalities amidst axonal htt aggregation places a cumulative burden upon
normal neuronal function under stressful conditions.

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