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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Gubitz, Amelie
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Johns Hopkins University
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Martin, Lee J; Wong, Margaret (2017) Enforced DNA repair enzymes rescue neurons from apoptosis induced by target deprivation and axotomy in mouse models of neurodegeneration. Mech Ageing Dev 161:149-162
Chang, Qing; Martin, Lee J (2016) Voltage-gated calcium channels are abnormal in cultured spinal motoneurons in the G93A-SOD1 transgenic mouse model of ALS. Neurobiol Dis 93:78-95
Chavez-Valdez, Raul; Flock, Debbie L; Martin, Lee J et al. (2016) Endoplasmic reticulum pathology and stress response in neurons precede programmed necrosis after neonatal hypoxia-ischemia. Int J Dev Neurosci 48:58-70
Fayzullina, Saniya; Martin, Lee J (2016) DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy. J Neuropathol Exp Neurol 75:889-902
Fayzullina, Saniya; Martin, Lee J (2014) Detection and analysis of DNA damage in mouse skeletal muscle in situ using the TUNEL method. J Vis Exp :
Fayzullina, Saniya; Martin, Lee J (2014) Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA). PLoS One 9:e93329
Martin, Lee J; Fancelli, Daniele; Wong, Margaret et al. (2014) GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis. Front Cell Neurosci 8:433
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

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