Analysis of axonal transport and molecular chaperones during neurodegeneration in drosophila

Abstract

Neuronal dysfunction and cell death occurs during neurodegeneration. Animal models that express human disease genes and show neurodegenerative-like pathologies are widely used to study particular molecular systems in early neurodegenerative changes. Axonal transport (AT) is perturbed in several prevalent neurodegenerative diseases. The development of a Huntington’s Disease (HD) model in Drosophila melanogaster larvae is described, in which disease gene expression is directed to motor neurons (Chapter 2). This results in stalling and accumulation of AT vesicles in live animals and a locomotion defect after additional environmental stress. The cause of AT disruption and neuronal dysfunction in most cases of neurodegeneration is unknown, but it is associated with protein misfolding and aggregation that overrides cellular defences such as the heat shock protein (HSP) molecular chaperone system. In addition to HD, this applies to human tauopathies such as Alzheimer’s Disease (AD), which involve axonal misfolding and aggregation of tau. Increased throughput assays to test larval locomotion are developed (Chapter 3) in a Drosophila larval model of tauopathy, in which locomotion defects are detectable under normal environmental conditions. Candidate chemical modulation of this locomotion phenotype is described that targets HSP induction (Chapter 4). The chemicals used result in no detectable change in hsp70 level, lower total tau levels, and worsening of the locomotion defect phenotype. Tissue-specific elevation of hsp70 after hypoxic stress (Chapter 5) protects from acute behavioural disability and reduced survival in aged adult Drosophila expressing human tau in the nervous system. These studies indicate some therapeutic potential for HSP elevation in tau mediated pathology. Nevertheless, further work is required if chemical chaperone induction, and the roles of HSPs in axonal transport and homeostasis during chronic neurodegenerative and acute environmental stress, are to be further explored in these models

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