title: 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.
authors.affiliation: University of Southampton, Bassett Crescent East, UK.
authors.forename: C
authors.initials: C
authors.lastname: Sinadinos
authors.forename: T
authors.initials: T
authors.lastname: Burbidge-King
authors.forename: D
authors.initials: D
authors.lastname: Soh
authors.forename: L M
authors.initials: LM
authors.lastname: Thompson
authors.forename: J L
authors.initials: JL
authors.lastname: Marsh
authors.forename: A
authors.initials: A
authors.lastname: Wyttenbach
authors.forename: A K
authors.initials: AK
authors.lastname: Mudher
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001831:Body Temperature / Q000235:genetics; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020233:Gait Disorders, Neurologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018882:Heat Stress Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D022161:Transport Vesicles / Q000378:metabolism / Q000473:pathology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine