Chai, Andrea Ying Ying

2018-03-29T12:15:29Z

2018-03-29T12:15:29Z

2010

Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by selective death of motor neurons leading to spasticity, muscle wasting and paralysis. Human VAMP-associated protein B (hVAPB) is the causative gene of a clinically diverse group of MNDs including amyotrophic lateral sclerosis (ALS), atypical ALS and late-onset spinal muscular atrophy. The pathogenic mutation is inherited in a dominant manner. Drosophila VAMP-associated protein of 33 kDa A (DVAP-33A) is the structural homologue of hVAPB and regulates synaptic remodeling by affecting the size and number of boutons at neuromuscular junctions (NMJs). Associated with these structural alterations are compensatory changes in the physiology and ultrastructure of synapses, which maintain evoked responses within normal boundaries. DVAP-33A and hVAPB are functionally interchangeable and transgenic expression of mutant DVAP-33A in neurons recapitulates major hallmarks of the human disease including locomotion defects, neuronal death and aggregate formation. Aggregate accumulation is accompanied by a depletion of the endogenous protein from its normal localization. These findings pinpoint to a possible role of hVAPB in synaptic homeostasis. To elucidate the patho-physiology underlying motor neuron degeneration in humans, we also generated a Drosophila model of ALS8 in the adult eye. Targeted expression of mutant DVAP-33A in the Drosophila compound eye causes a degenerative phenotype characterized by a smaller eye containing missing or aberrantly oriented bristles and fused ommatidia. In a F1 deficiency screen, we performed a genome-wide survey aimed at identifying enhancers and suppressors of the degenerative eye phenotype. Several interacting regions have been found and the identification of these interacting genes will shed new light on the molecular mechanisms underlying VAP-induced ALS.

http://hdl.handle.net/1842/29055

The University of Edinburgh

Annexe Thesis Digitisation Project 2018 Block 17

Already catalogued

Drosophila as a tool to identify genes and mechanisms involved in Amyotrophic Lateral Sclerosis

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy