Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin

Bethany L. Johnson-Kerner, Faizzan S. Ahmad, Alejandro Garcia Diaz, John Palmer Greene, Steven J. Gray, Richard Jude Samulski, Wendy K. Chung, Rudy Van Coster, Paul Maertens, Scott A. Noggle, Christopher E. Henderson, Hynek Wichterle

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    17 Citations (Scopus)

    Abstract

    Giant axonal neuropathy (GAN) is a progressive neurodegenerative disease caused by autosomal recessive mutations in the GAN gene resulting in a loss of a ubiquitously expressed protein, gigaxonin. Gene replacement therapy is a promising strategy for treatment of the disease; however, the effectiveness and safety of gigaxonin reintroduction have not been tested in human GAN nerve cells. Herewe report the derivation of induced pluripotent stem cells (iPSCs) from three GAN patients with different GAN mutations. Motor neurons differentiated from GAN iPSCs exhibit accumulation of neurofilament (NF-L) and peripherin (PRPH) protein and formation of PRPH aggregates, the key pathological phenotypes observed in patients. Introduction of gigaxonin either using a lentiviral vector or as a stable transgene resulted in normalization of NEFL and PRPH levels in GAN neurons and disappearance of PRPH aggregates. Importantly, overexpression of gigaxonin had no adverse effect on survival of GAN neurons, supporting the feasibility of gene replacement therapy. Our findings demonstrate that GAN iPSCs provide a novel model for studying human GAN neuropathologies and for the development and testing of new therapies in relevant cell types.

    Original languageEnglish
    Pages (from-to)1420-1431
    Number of pages12
    JournalHuman Molecular Genetics
    Volume24
    Issue number5
    DOIs
    Publication statusPublished - 1 Mar 2015

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    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)
    • Molecular Biology

    Cite this

    Johnson-Kerner, B. L., Ahmad, F. S., Diaz, A. G., Greene, J. P., Gray, S. J., Samulski, R. J., Chung, W. K., Van Coster, R., Maertens, P., Noggle, S. A., Henderson, C. E., & Wichterle, H. (2015). Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin. Human Molecular Genetics, 24(5), 1420-1431. https://doi.org/10.1093/hmg/ddu556