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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axonal Transport / genetics*
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Axons / metabolism*
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Axons / pathology
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Body Temperature / genetics
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Central Nervous System / metabolism*
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Central Nervous System / pathology
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Central Nervous System / physiopathology
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Drosophila / genetics
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Drosophila / metabolism*
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Female
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Gait Disorders, Neurologic / genetics
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Gait Disorders, Neurologic / metabolism
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Gait Disorders, Neurologic / physiopathology
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Heat Stress Disorders / genetics
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Heat Stress Disorders / metabolism
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Heat Stress Disorders / physiopathology
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Humans
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Huntingtin Protein
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Huntington Disease / genetics
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Huntington Disease / metabolism
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Huntington Disease / physiopathology
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Male
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Motor Neurons / metabolism*
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Motor Neurons / pathology
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism*
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism*
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Peptides / genetics
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Peptides / metabolism
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Stress, Physiological / genetics
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Transport Vesicles / metabolism
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Transport Vesicles / pathology
Substances
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HTT protein, human
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Huntingtin Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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polyglutamine