F4‐04‐04: Subcortical Shape Analysis for Joint Biomarker Discovery

not available. PL-04-02 GENOMIC ANALYSIS OF NEURODEGENERATION GIVES CLUES TO PATHWAYS TO SELECTIVE CELL LOSS: THE HYPOTHESIS OF THE CATASTROPHIC CLIFF OF NEURON FAILURE John Hardy, UCL Institute of Neurology, London, United Kingdom. Contact e-mail: j.hardy@ucl.ac.uk Background:As we identify large numbers of genes involved in different syndromes, we are realising that these genes mark specific biochemical pathways. In Alzheimer’s disease, these are APP processing, cholesterol metabolism, microglial/monocyte activation and the ubiquitin proteasome system. In Parkinson’s disease, they are autophagy and mitophagy. Methods: The simplest interpretation of these data is that genetic variability in these pathways influences disease risk and that pharmacologic manipulation of these pathways constitute valid targets for their treatment. A deeper truth, however, also appears to come from this richness of genetic data: as we identify multiple genes for syndromes, we see that different neutron types fail in the context different lesions. Results: These catastrophic failure points include calcium homeostasis and DNA repair for Purkinje cells, the ubiquitin proteasome system for granule cells, mitochondrial complex 1 for nigral neurons, the lysosome for cortical pyramidal neurons, and the ubiquitin proteasome system for the cortical pyramidal neurons and motor neurons and RNA processing for motor neurons. Conclusions: Thus, each of these cell types is prone to be closer to failure under different stressors. Understanding these selective weaknesses offers a route to the development of rational neuroprotective strategies. WEDNESDAY, JULY 27, 2016