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Hum Mol Genet. 2016 Jun 1;25(11):2143-2157. Epub 2016 Mar 21.

Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy.

Author information

1
Davee Department of Neurology.
2
Department of Pediatrics.
3
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
4
Department of Biology, Portland State University, Portland, OR, USA and.
5
Research Centre of IUSMQ, Department of Psychiatry and Neuroscience of Laval University, Quebec, QC, G1V 0A6, Canada.
6
Department of Cell and Molecular Biology.
7
Davee Department of Neurology, Department of Cell and Molecular Biology, p-opal@northwestern.edu.

Abstract

Intermediate filaments (IFs) are cytoskeletal polymers that extend from the nucleus to the cell membrane, giving cells their shape and form. Abnormal accumulation of IFs is involved in the pathogenesis of number neurodegenerative diseases, but none as clearly as giant axonal neuropathy (GAN), a ravaging disease caused by mutations in GAN, encoding gigaxonin. Patients display early and severe degeneration of the peripheral nervous system along with IF accumulation, but it has been difficult to link GAN mutations to any particular dysfunction, in part because GAN null mice have a very mild phenotype. We therefore established a robust dorsal root ganglion neuronal model that mirrors key cellular events underlying GAN. We demonstrate that gigaxonin is crucial for ubiquitin-proteasomal degradation of neuronal IF. Moreover, IF accumulation impairs mitochondrial motility and is associated with metabolic and oxidative stress. These results have implications for other neurological disorders whose pathology includes IF accumulation.

PMID:
27000625
PMCID:
PMC5081048
DOI:
10.1093/hmg/ddw081
[Indexed for MEDLINE]
Free PMC Article

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