PhD in Dementia Research - Characterising the pathways to abnormal protein aggregation in dementia in Drosophila and induced pluripotent stem cell models

Dementias are characterised by the aggregation of proteins in neuronal cells. These occur in multiple diseases where the build up of insoluble proteinaceous inclusions inside or outside cells is commonly seen. In rare, familial, forms of many neurodegenerations we know that such aggregates often contain a mutated gene product: mutant huntingtin inclusions in Huntington’s disease (HD); mutant beta-amyloid proteins in Alzheimer’s disease (AD) and mutant alpha synuclein protein in Parkinson’s disease (PD), for instance. In sporadic AD and PD beta-amyloid and alpha-synuclein inclusions are also seen despite the absence of familial mutations. The formation of the proteinaceous aggregates is dynamic, with synthesis and clearance of the proteins and their structure all influencing disease pathogenesis. We have evidence in HD that specific amino acid changes in genes of the autophagy pathway lead to early onset of disease. We wish to examine the effects of knocking out the genes containing these changes and to directly model these specific changes in the orthologous proteins in HD mutant Drosophila models. If the changes lead to altered dynamics or clearance of mutant huntingtin we will characterise the kinetics of this effect in flies using assays of autophagy. These include the signalling pathways triggering activation of autophagy, the machinery governing formation of autophagic vacuoles and the processes leading to their clearance by lysosomes. We will go on to characterise the relevant pathway using the same variants in fly models of AD and PD to investigate whether this constitutes a common pathway for clearance of mutant aggregated proteins. These results will then be validated in induced pluripotent stem cell models.