Testing Metformin as a therapy for Giant Axonal Neuropathy

Project: Research project

Project Details


Giant Axonal Neuropathy (GAN) is caused by mutations in the E3 ligase adaptor gigaxonin— a protein that degrades neurofilaments (1). Using a dorsal root ganglion cell model from GAN null mice, we have discovered two major pathological consequences of resulting neurofilament accumulation: First, mitochondrial transport is hampered; this in turn results in bioenergetic abnormalities visible as increased oxygen consumption and generation of toxic reactive oxygen species (Figure 1; 2)). Second, a similar disruption in lysosomal motility (and potentially from gigaxonin playing a more direct role in autophagic regulation) leads to deficits in autophagy (Figure 2). In this context, we were intrigued by a recent high-throughput screen by our collaborator Dr. Natasha Snider, University of North Carolina. She discovered metformin—a drug that has significant beneficial effects in other metabolic conditions— as one of only 12 drugs (among 1594) to significantly improve the GAN phenotype (Figure 3). Metformin is an FDA approved metabolic enhancer, particularly in diabetes, through its effects on mitochondria and autophagic pathways. The molecular mechanism by which metformin functions is still debated; however, recent studies suggests that it stimulates AMP kinase by increasing the phosphorylation of one of its catalytic subunits (3). This activation promotes mitochondrial fission and thus improves mitochondrial membrane potential and respiration (3). AMPK also upregulates autophagic activity by phosphorylating inc-51-like kinase and Beclin-1, key players in the early stages of autophagic activation (4). These effects on mitochondria and autophagy would be expected to ameliorate the GAN phenotype. In this proposal, therefore, we will test metformin’s potential for GAN using both in vitro and in vivo approaches linking work from the Snider and Opal labs.
Effective start/end date12/1/2011/30/21


  • Hannah's Hope for Giant Axonal Neuropathy, Inc. (Opal AGMT 8/27/21)


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