Amyotrophic lateral sclerosis (ALS) is the 3rd most common human neurodegenerative disease with an adult onset. It is a fatal paralytic disease of motor neurons (MNs) without any effective treatments. Novel mechanism-based targets need to be identified for drug discovery relevant to diseased MNs. Some forms of ALS are inherited and are caused by mutations in the superoxide dismutase-1 (SOD1) gene, thus providing a clue about MN vulnerability. Many different SOD1 mutations occur, but the mechanisms of human SOD1 (hSOD1) toxicity to MNs are unresolved. Importantly, the autonomy of the MN degeneration in ALS is an important unresolved problem. We hypothesize that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. We have created new transgenic (tg) mice with skeletal muscle-specific expression of hSOD1 gene variants. These hSOD1mus tg mice develop neurologic and pathologic phenotypes consistent with ALS. Using these novel mice we propose to study skeletal muscle as a disease-causing entity in ALS.
In Aim 1 we will analyze the age-related neurologic and pathologic phenotypes of hSOD1mus tg mice. We hypothesize that the mechanisms of MN degeneration in our hSOD1mus tg mice are consistent with distal axonopathy and target deprivation-induced apoptosis.
In Aim 2, we will analyze the involvement of oxidative stress and activation of the mitochondrial permeability pore in skeletal muscle as mediators of muscle pathology in hSOD1mus tg mice.
In Aim 3 we will use cultured cells to examine if hSOD1 expression in skeletal muscle cells alters their intracellular redox state, Ca2+ handling, and ion channel function and disrupts the neuromuscular junction, thus provoking MN degeneration. The work can lead to new concepts about the non-autonomous death of MNs in ALS pathogenesis. The discovery of instigating toxicities or disease progression determinants within skeletal muscle would be very valuable for development of new effective therapies in the treatment and cure of ALS.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder. This work will determine if abnormalities in skeletal muscle have causal roles in the disease mechanisms. Skeletal muscle could provide new tissue- and molecular targets for drug discovery in ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065895-03
Application #
8212194
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Gubitz, Amelie
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$351,575
Indirect Cost
$137,200
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Martin, Lee J; Wong, Margaret (2013) Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms. Neurotherapeutics 10:722-33
Martin, Lee J (2012) Biology of mitochondria in neurodegenerative diseases. Prog Mol Biol Transl Sci 107:355-415
Martin, Lee J; Chang, Qing (2012) Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis. Mol Neurobiol 45:30-42
Gertz, Barry; Wong, Margaret; Martin, Lee J (2012) Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice. J Neuropathol Exp Neurol 71:162-77
Chestnut, Barry A; Chang, Qing; Price, Ann et al. (2011) Epigenetic regulation of motor neuron cell death through DNA methylation. J Neurosci 31:16619-36
Martin, Lee J (2011) Mitochondrial pathobiology in ALS. J Bioenerg Biomembr 43:569-79
Chang, Qing; Martin, Lee J (2011) Glycine receptor channels in spinal motoneurons are abnormal in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 31:2815-27
Chang, Qing; Martin, Lee J (2011) Motoneuron subtypes show specificity in glycine receptor channel abnormalities in a transgenic mouse model of amyotrophic lateral sclerosis. Channels (Austin) 5:299-303
Wang, Yi; Pan, Yan; Price, Ann et al. (2011) Generation and characterization of transgenic mice expressing mitochondrial targeted red fluorescent protein selectively in neurons: modeling mitochondriopathy in excitotoxicity and amyotrophic lateral sclerosis. Mol Neurodegener 6:75

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