Analysis of novel pathways in neurodegeneration using mouse and fly model organisms

The aim of this project was to understand the molecular mechanisms underlying movement disorders and to identify new genes involved in neurodegeneration. By genetic crossing two mutations identified in the Shakin' Stevens mouse, were separated into individual mouse strains. Both have provided important new insights into two pathways characteristic of neurodegeneration: The autophagy-lysosome pathway, a protein degradation pathway in the Nymphe mouse (nym/nym), and lipid metabolism defects in the Jabber mouse (jab/+). The nym homozygous mouse was identified as a novel mouse model of the lysosomal storage disorder mucolipidosis II (MLII) homozygous for a patient mutation in the GNPTAB gene. The novel mouse model of MLII more fully recapitulates the human pathology than the previously described Gnptab knock-out mouse. Histological analysis of the brain revealed for the first time progressive neurodegeneration in the cerebellum with severe Purkinje cell loss. In addition, based on similar features between Niemann-Pick type C disease and MLII, the nym homozygous mice were treated with 2-hydroxypropyl-β-cyclodextrin, a drug previously reported to rescue Purkinje cell death in a mouse model of NPC disease. No improvement in brain pathology was observed, demonstrating that cerebellar degeneration is not primarily triggered by loss of Npc2 function. The jab mouse model, harbouring a mutation in the small GTPase Arl1, was characterised as a novel model of chylomicron retention disease, a lipoprotein deficiency, and offered the opportunity to study a novel gene involved in the maintenance of lipid homeostasis and neurodegeneration, specifically demyelination in the peripheral nervous system. The jab mutation in Drosophila presented with characteristic features of the jab mouse, highlighting the functional conservation of Arl1 and validated the use of Drosophila for further studies. Interestingly, together with constitutively active and inactive mutants, pathology in lipid droplet formation and defective insulin signalling was associated with defective Arl1 function. Using Drosophila will enable further studies into Arl1's role in tissue specific function and help elucidate molecular pathway leading to demyelination. Thus, this work has highlighted the value of a phenotype-driven approach to investigate novel neurodegenerative pathways and their amenability to therapy.