It has an ungainly name and an uglier phenotype. Giant Axon Neuropathy (GAN) is an extremely rare genetic disease that manifests itself in children under five as a distinctive waddling walk. On the cellular level, the signature of GAN is a pile-up of aggregates and bundles of intermediate fibers (IFs) in neuronal axons, first peripherally but eventually in the central nervous system. Over time, the damage progresses into loss of sensation, coordination, and strength until in the second decade of life, most sufferers are in wheelchairs. Only a few will survive into their 20s.
The disorder has long been linked to a bewildering variety of mutations in the GAN gene that all affect the production of gigaxonin, an E3 ligase that normally clears unwanted IF aggregates from the axon. But another cellular symptom of GAN is the chaotic distribution and motility of mitochondria so the question remained, was GAN driving a separate pathogenic process in mitochondria? No, says Jason Lowery and colleagues at Northwestern’s Feinberg School of Medicine in the laboratory of ASCB member Robert D. Goldman. Reporting in the February 15 issue of Molecular Biology of the Cell, the researchers show that it’s the IF logjam caused by defective gigaxonin that is wreaking collateral damage on the mitochondria. Most dramatically, they report that expressing wild-type gigaxonin in cultured GAN fibroblasts rescues mitochondrial motility. Other Northwestern collaborators include Anne Goldman, Nikhil Jain, Edward Kuczmarski, and ASCB member Vladimir Gelfand plus others at ETH Zurich and McMaster University in Canada.