Role of Gigaxonin in the Regulation of Intermediate Filaments: a Study Using Giant Axonal Neuropathy Patient-Derived Induced Pluripotent Stem Cell-Motor Neurons
type: CreativeWork
description: Patients with giant axonal neuropathy (GAN) exhibit loss of motor and sensory function and typically live for less than 30 years. GAN is caused by autosomal recessive mutations leading to low levels of gigaxonin, a ubiquitously-expressed cytoplasmic protein whose cellular roles are poorly understood. GAN pathology is characterized by aggregates of intermediate filaments (IFs) in multiple tissues. Disorganization of the neuronal intermediate filament (nIF) network is a feature of several neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease and axonal Charcot-Marie-Tooth disease. In GAN such changes are often striking: peripheral nerve biopsies show enlarged axons with accumulations of neurofilaments; so called "giant axons." Interestingly, IFs also accumulate in other cell types in patients. These include desmin in muscle fibers, GFAP (glial fibrillary acidic protein) in astrocytes, and vimentin in multiple cell types including primary cultures of biopsied fibroblasts. These findings suggest that gigaxonin may be a master regulator of IFs, and understanding its function(s) could shed light on GAN as well as the numerous other diseases in which IFs accumulate. However, an interaction between gigaxonin and IFs has not been detected and how IF accumulation is triggered in the absence of functional gigaxonin has not been determined. To address these questions I undertook a proteomic screen to identify the normal binding partners of gigaxonin. Prominent among them were several classes of IFs, including the neurofilament subunits whose accumulation leads to the axonal swellings for which GAN is named. Strikingly, human motor neurons (MNs) differentiated from GAN iPSCs recapitulate this key phenotype. Accumulation of nIFs can be rescued by reintroduction of gigaxonin, by viral delivery or genetic correction. GAN iPS-MNs do not display survival vulnerability in the presence of trophic factors, but do display increased cell death in the pr…
abstract: Patients with giant axonal neuropathy (GAN) exhibit loss of motor and sensory function and typically live for less than 30 years. GAN is caused by autosomal recessive mutations leading to low levels of gigaxonin, a ubiquitously-expressed cytoplasmic protein whose cellular roles are poorly understood. GAN pathology is characterized by aggregates of intermediate filaments (IFs) in multiple tissues. Disorganization of the neuronal intermediate filament (nIF) network is a feature of several neurodegenerative disorders, including amyotrophic lateral sclerosis, Parkinson's disease and axonal Charcot-Marie-Tooth disease. In GAN such changes are often striking: peripheral nerve biopsies show enlarged axons with accumulations of neurofilaments; so called "giant axons." Interestingly, IFs also accumulate in other cell types in patients. These include desmin in muscle fibers, GFAP (glial fibrillary acidic protein) in astrocytes, and vimentin in multiple cell types including primary cultures of biopsied fibroblasts. These findings suggest that gigaxonin may be a master regulator of IFs, and understanding its function(s) could shed light on GAN as well as the numerous other diseases in which IFs accumulate. However, an interaction between gigaxonin and IFs has not been detected and how IF accumulation is triggered in the absence of functional gigaxonin has not been determined. To address these questions I undertook a proteomic screen to identify the normal binding partners of gigaxonin. Prominent among them were several classes of IFs, including the neurofilament subunits whose accumulation leads to the axonal swellings for which GAN is named. Strikingly, human motor neurons (MNs) differentiated from GAN iPSCs recapitulate this key phenotype. Accumulation of nIFs can be rescued by reintroduction of gigaxonin, by viral delivery or genetic correction. GAN iPS-MNs do not display survival vulnerability in the presence of trophic factors, but do display increased cell death in the pr…
author: Johnson-Kerner, Bethany
language: English
keywords: Cytoplasmic filaments, Nervous system--Diseases, Nervous system--Degeneration, Motor neurons, Neuropathy, Neurosciences, Cytology
date published: 2013
date modified: 2026-07-24T01:44:23Z
provider: Columbia University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Columbia University

PropertyValue
property ID: DOI
value: 10.7916/D8Z324C3