Translational studies in Giant axonal neuropathy

Giant axonal neuropathy (GAN) is a recessive disease that presents in childhood with a clumsy gait and a loss of peripheral strength and sensation. Eventually the disease attacks the central nervous system and cranial nerves. GAN is caused by mutations in both alleles of the GAN gene, which encodes gigaxonin (also, rather confusingly, known as GAN): The disease-causing mutations (~50 so far, including deletions, insertions, and point mutations throughout the gene) and the autosomal recessive inheritance suggested that GAN is caused by a loss of function (1), but specifically what that lost function was has remained elusive up until now. We have compelling evidence that suggests GAN governs the degradation of neurofilaments (NF) by the ubiquitin- proteasomal system (2). NF accumulation is clearly toxic—overexpression of NFs in mice is sufficient to cause neurodegeneration (3-5)— but the pathogenic cascade is unclear. In order to identify possible therapeutic pathways, we propose an unbiased high-throughput screen of small molecules and RNAi libraries on DRGs (which will then be validated in iPSCs) measuring NF aggregate clearance.