Giant axonal neuropathy (GAN) is an autosomal recessive neurodegenerative disease that strikes early in life with symptoms of progressive neuropathy, cognitive decline, seizures, and ataxia. GAN is a devastating and incurable disease with patients dying in the second decade of life. It is caused by mutations of the GAN gene, which encodes gigaxonin, a member of the BTB/Kelch family of E3 ligase adaptors. These proteins are responsible for ubiquitinating proteins to be degraded via the proteasome. We discovered that neuronal intermediate filaments (NFs) are a major class of substrates for gigaxonin (Israeli et al. Human Molecular Genetics, 2016; Mahammad et al. The Journal of Clinical Investigation, 2013; Opal et al. Rare diseases, 2013). The overarching hypothesis of this proposal is that GAN mutations prevent gigaxonin from degrading NFs; neurons swell with NF accumulations, distending the neurites and giving the disease its apt name. In addition, the combination of peripheral and cranial neuropathy combined with CNS lesions is reminiscent of several well-known mitochondrial neuropathies, and we have found that, in GAN, mitochondria (and other organelles such as lysosomes) are no longer able to travel along neurites; instead they get stuck in and around the enormous NF aggregates. This would suggest that depleting NFs should prevent downstream pathology, which we will test using genetic and pharmacological approaches.
|Effective start/end date||2/1/19 → 12/31/22|
- Muscular Dystrophy Association (Award Signed 1/14/19)
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