Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice
Open Access
- 10 March 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (11), 2284-2302
- https://doi.org/10.1093/hmg/ddq106
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons (MNs) that causes skeletal muscle paralysis. Familial forms of ALS are linked to mutations in the superoxide dismutase-1 (SOD1) gene. The mechanisms of human SOD1 (hSOD1) toxicity to MNs are unknown. We hypothesized that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. We created transgenic (tg) mice expressing wild-type-, G37R- and G93A-hSOD1 gene variants only in skeletal muscle. These tg mice developed age-related neurologic and pathologic phenotypes consistent with ALS. Affected mice showed limb weakness and paresis with motor deficits. Skeletal muscles developed severe pathology involving oxidative damage, protein nitration, myofiber cell death and marked neuromuscular junction (NMJ) abnormalities. Spinal MNs developed distal axonopathy and formed ubiquitinated inclusions and degenerated through an apoptotic-like pathway involving capsase-3. Mice expressing wild-type and mutant forms of hSOD1 developed MN pathology. These results demonstrate that human SOD1 in skeletal muscle has a causal role in ALS and identify a new non-autonomous mechanism for MN degeneration explaining their selective vulnerability. The discovery of instigating molecular toxicities or disease progression determinants within skeletal muscle could be very valuable for the development of new effective therapies for the treatment and cure of ALS.Keywords
This publication has 74 references indexed in Scilit:
- The mitochondrial permeability transition pore: A molecular target for amyotrophic lateral sclerosis therapyBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010
- Hyperactive Intracellular Calcium Signaling Associated with Localized Mitochondrial Defects in Skeletal Muscle of an Animal Model of Amyotrophic Lateral SclerosisJournal of Biological Chemistry, 2010
- Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS miceBrain Structure and Function, 2009
- The mitochondrial permeability transition pore in motor neurons: Involvement in the pathobiology of ALS miceExperimental Neurology, 2009
- Gamma and alpha motor neurons distinguished by expression of transcription factor Err3Proceedings of the National Academy of Sciences of the United States of America, 2009
- Muscle Mitochondrial Uncoupling Dismantles Neuromuscular Junction and Triggers Distal Degeneration of Motor NeuronsPLOS ONE, 2009
- Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosisProceedings of the National Academy of Sciences of the United States of America, 2006
- Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosisProceedings of the National Academy of Sciences of the United States of America, 2006
- Manganese Superoxide Dismutase Levels Are Elevated in a Proportion of Amyotrophic Lateral Sclerosis Patient Cell LinesBiochemical and Biophysical Research Communications, 2000
- Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosisNature, 1993