Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation

Saleemulla Mahammad, S. N. Prasanna Murthy, Alessandro Didonna, Boris Grin, Eitan Israeli, Rodolphe Perrot, Pascale Bomont, Jean Pierre Julien, Edward Kuczmarski, Puneet Opal, Robert D. Goldman*

*Corresponding author for this work

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Giant axonal neuropathy (GAN) is an early-onset neurological disorder caused by mutations in the GAN gene (encoding for gigaxonin), which is predicted to be an E3 ligase adaptor. In GAN, aggregates of intermediate filaments (IFs) represent the main pathological feature detected in neurons and other cell types, including patients' dermal fibroblasts. The molecular mechanism by which these mutations cause IFs to aggregate is unknown. Using fibroblasts from patients and normal individuals, as well as Gan-/- mice, we demonstrated that gigaxonin was responsible for the degradation of vimentin IFs. Gigaxonin was similarly involved in the degradation of peripherin and neurofilament IF proteins in neurons. Furthermore, proteasome inhibition by MG-132 reversed the clearance of IF proteins in cells overexpressing gigaxonin, demonstrating the involvement of the proteasomal degradation pathway. Together, these findings identify gigaxonin as a major factor in the degradation of cytoskeletal IFs and provide an explanation for IF aggregate accumulation, the subcellular hallmark of this devastating human disease.

Original languageEnglish (US)
Pages (from-to)1964-1975
Number of pages12
JournalJournal of Clinical Investigation
Volume123
Issue number5
DOIs
StatePublished - May 1 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Mahammad, S., Prasanna Murthy, S. N., Didonna, A., Grin, B., Israeli, E., Perrot, R., Bomont, P., Julien, J. P., Kuczmarski, E., Opal, P., & Goldman, R. D. (2013). Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. Journal of Clinical Investigation, 123(5), 1964-1975. https://doi.org/10.1172/JCI66387