Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice

Neurodegeneration in an inherited form of ALS is non-cell-autonomous, with ALS-causing mutant SOD1 damage developed within multiple cell types. Selective inactivation within motor neurons of an ubiquitously expressed mutant SOD1 gene has demonstrated that mutant damage within motor neurons is a dete...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-03, Vol.106 (11), p.4465-4470
Main Authors: Lobsiger, Christian S, Boillee, Severine, McAlonis-Downes, Melissa, Khan, Amir M, Feltri, M. Laura, Yamanaka, Koji, Cleveland, Don W
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - pathology
Amyotrophic Lateral Sclerosis - prevention & control
Animals
Astrocytes
Axons
Biological Sciences
Cells
Disease Models, Animal
Disease Progression
Down-Regulation
Gene expression
Insulin-Like Growth Factor I - biosynthesis
Mice
Motor neuron disease
Motor neurons
Mutation
Nervous system diseases
Neuroglia
Neurons
Neurons - metabolism
Rodents
Schwann cells
Schwann Cells - metabolism
Sciatic nerve
Superoxide Dismutase - biosynthesis
Superoxide Dismutase - physiology
Superoxide Dismutase-1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Neurodegeneration in an inherited form of ALS is non-cell-autonomous, with ALS-causing mutant SOD1 damage developed within multiple cell types. Selective inactivation within motor neurons of an ubiquitously expressed mutant SOD1 gene has demonstrated that mutant damage within motor neurons is a determinant of disease initiation, whereas mutant synthesis within neighboring astrocytes or microglia accelerates disease progression. We now report the surprising finding that diminished synthesis (by 70%) within Schwann cells of a fully dismutase active ALS-linked mutant (SOD1G³⁷R) significantly accelerates disease progression, accompanied by reduction of insulin-like growth factor 1 (IGF-1) in nerves. Coupled with shorter disease duration in mouse models caused by dismutase inactive versus dismutase active SOD1 mutants, our findings implicate an oxidative cascade during disease progression that is triggered within axon ensheathing Schwann cells and that can be ameliorated by elevated dismutase activity. Thus, therapeutic down-regulation of dismutase active mutant SOD1 in familial forms of ALS should be targeted away from Schwann cells.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0813339106