title: Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy.
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.
authors.affiliation: Davee Department of Neurology.
authors.forename: Eitan
authors.initials: E
authors.lastname: Israeli
authors.affiliation: Davee Department of Neurology.
authors.forename: Dilyan I
authors.initials: DI
authors.lastname: Dryanovski
authors.affiliation: Department of Pediatrics.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Schumacker
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.affiliation: Department of Biology, Portland State University, Portland, OR, USA and.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Singer
authors.affiliation: Research Centre of IUSMQ, Department of Psychiatry and Neuroscience of Laval University, Quebec, QC, G1V 0A6, Canada.
authors.forename: Jean P
authors.initials: JP
authors.lastname: Julien
authors.affiliation: Department of Cell and Molecular Biology.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Goldman
authors.affiliation: Davee Department of Neurology, Department of Cell and Molecular Biology, p-opal@northwestern.edu.
authors.forename: Puneet
authors.initials: P
authors.lastname: Opal
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D056768:Giant Axonal Neuropathy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis / Q000235:genetics*; D007382:Intermediate Filaments / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis
chemical_list: D003598:Cytoskeletal Proteins; C501171:Gan protein, mouse; D007381:Intermediate Filament Proteins; D046988:Proteasome Endopeptidase Complex