Special LMNN Seminar - Converging pathways in fatty acylation, autophagy, and neurodegeneration

My research goal is to identify points of convergence in pathways that reduce mutant proteins that can be applied broadly to develop therapeutic strategies for neurodegenerative diseases. Many neurodegenerative diseases share common pathogenic processes. Often genetic mutations result in dysregulated protein clearance pathways leading to neuronal cell death in particular brain regions and specific clinical phenotypes. An emerging goal in the treatment of many neurodegenerative diseases is to reduce the levels of toxic mutant and/or aggregated proteins. Autophagy is an essential pathway that removes toxic proteins and damaged organelles from the cell, but is disrupted in many neurodegenerative diseases, leading to build up of toxic and aggregated proteins. However, autophagy is dysfunctional in many forms of neurodegeneration. My previous research focused on repairing autophagy in the neurodegenerative disease Huntington disease (HD) to promote clearance of the mutant huntingtin protein. In doing so, I have identified palmitoylation as a potential unifying mechanism in autophagy and neurodegeneration. Although many regulators of autophagy are known, how they rapidly transition from the cytoplasm to their target membranes upon autophagy activation is not well understood. Palmitoylation is a dynamic post-translational modification, similar to phosphorylation, involving the reversible addition of a fatty acid, palmitate, to cysteine residues. The hydrophobic lipid promotes membrane binding, protein-protein interactions, and protein stability. Palmitoylation appears to provide a rapid and dynamic mechanism for membrane recruitment of autophagy regulators to promote mutant protein clearance during autophagy.