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Genomic analysis of neurodegeneration (Professor John Hardy, Department of Neurodegenerative Diseases, IoN, UCL)
We have the luxury of unprecedented genetic clues as to the aetiology of the major neruodegenerative disease: Alzheimer’s disease, Parkinson’s disease and the tauopathies. In all cases gene duplications of the deposited proteins (APP/Ab,, synuclein and tau) can lead to disease. This shows that these proteins are close to a critical solubility threshold. Other mutations, for exacmple in presenilin, alter APP processing such that either more Ab or a less soluble Ab are produced. Pathogenic tau mutations also result in a less soluble tau isoform being produced and normal genetic variability at the tau and synuclein loci also predispose to disease. However, most of the risk loci we are finding for disease is involved in the clearance of these deposited protein: in AD, the clearance involved the microglial response to memebrane damage: in Parkinson’s disease, it is lysosome insufficiency and synuclein is largely cleared through the lysosome and in the tauopathies, it is the ubiquitin proteasome pathway. Thus an overarching them emerging from these analyses is that they are predisposed to by either over production of the desposited proteins or by insuficiences in the clearance of these proteins. For therapies, this leads to the suggestions that we should be aiming to reduce the production of these proteins or potentiate their clearance.