John Hardy Reta Lila Weston Institute, University College London, Institute of Neurology, London, UK
Genomic analyses of the major neurodegenerative diseases, Alzheimer's disease, frontotemporal dementia, ALS and Parkinson's disease have driven major changes in our views of these diseases. In all cases, we have gone from knowing about 1-3 loci for the disease to now, having upwards of 15-20. This richness of information means we can now start to use these data to determine pathways towards neurodegeneration. I will argue that these pathways in general mark failures in damage repair. In Alzheimer's disease, I will argue that the major component of risk is the failure of microglial led membrane repair, with the membrane damage being largely driven by Ab species. In pure FTD, I will argue that lysosomal failure is at least a part of the pathogenesis. In ALS, most of the loci are involved in the RNA stress response, and in FTD/ALS most of the genes are involved in the ubiquitin proteasome system. In PD, many of the genes are involved in lysosomal biology whereas others are involved in mitophagy. I will argue that these failures suggest that different neurons are close to different failure points (“catastrophic cliffs”) and that these critical weaknesses are part of the reason for selective vulnerability.
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