Understanding pathophysiological mechanisms underlying neurodegeneration

Giant axonal neuropathy (GAN) is an early-onset, autosomal recessive neurodegenerative disease that impacts the central and peripheral nervous systems. Pathologically, GAN is characterized by the disorganization and aggregation of intermediate filaments (IF). Formed from self-assembling subunits, the IF network spans the cell from the nucleus to the periphery. In GAN many cell types show abnormalities in the organization of IF, but neurons clearly bear the brunt of the pathology. Axons swell with the accumulation of neuronal IF, and degenerate to cause the neurological symptoms of GAN. The gene mutated in GAN encodes gigaxonin, a protein that belongs to the BTB/Kelch family of E3 ligase-like adaptor proteins. These proteins typically play a role in ubiquitin-proteasome mediated protein degradation. Based on our own data, we hypothesize that IF aggregation creates steric roadblocks in neurites that interfere with intracellular transport of organelles such as mitochondria, resulting in downstream pathology. This proposal comprehensively tests this model; at the same time, we will mechanistically dissect the steps of neurofilament degradation by gigaxonin, an important cell biological problem in itself.