3P - Post Doc Seminar - 16 April Sara Saez Atienzar, NIA, postdoctoral fellow, discusses 'Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types' and Nikhil Panicker, Postdoctoral Fellow at Johns Hopkins University School of Medicine, presents on 'How Parkin limits priming and activation of the NLRP3 inflammasome in dopaminergic neurons' Sara presented on the challenges when studying complex diseases like ALS in understanding how to explore the biological pathways that underly the pathobiology of multitude of genes. To overcome this limitation, we have taken advantage of a novel large-scale analysis based on polygenic risk score that uses genome-wide data involving ~ 80,000 individuals to find the biological pathways and cell types involved in the disease. This hypothesis free approach provides substantial genetic evidence implicating cellular trafficking and cell and neural morphogenesis, as well as interneurons, as significant contributors to the pathogenesis of ALS. Nikhil discussed how the activation of the NLRP3 inflammasome is well-described in immune cells such as microglia. We found that adult onset depletion of the E-3 ligase Parkin within the dopaminergic (DA) neurons of the Substantia nigra is significant to activate the NLRP3 inflammasome in these cells, resulting in inflammasome-dependent neuron death. Parkin serves a dual role to limit DA neuron inflammasome activation. Inactivation of parkin in the pre-formed fibril (PFF) mouse model also facilitates DA neuron inflammasome activation. The molecular mechanisms that lead to neuronal priming and activation of the NLRP3 inflammasome will be discussed.