Skeletal Muscle Mechanisms of Disease in ALS

Summary

Principal Investigator: Lee Martin
Affiliation: Johns Hopkins University
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: -------------------- - -------------------2
more information: NIH RePORT

Top Publications

  1. pmc Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA)
    SANIYA FAYZULLINA
    Division of Neuropathology, Department of Pathology, and the Pathobiology Graduate Program, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
    PLoS ONE 9:e93329. 2014
  2. pmc Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms
    Lee J Martin
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD, 21205 2196, USA
    Neurotherapeutics 10:722-33. 2013
  3. pmc Biology of mitochondria in neurodegenerative diseases
    Lee J Martin
    Division of Neuropathology, Department of Pathology, The Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Prog Mol Biol Transl Sci 107:355-415. 2012
  4. pmc Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice
    Barry Gertz
    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 2196, USA
    J Neuropathol Exp Neurol 71:162-77. 2012
  5. pmc Epigenetic regulation of motor neuron cell death through DNA methylation
    Barry A Chestnut
    Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 2196, USA
    J Neurosci 31:16619-36. 2011
  6. pmc Mitochondrial pathobiology in ALS
    Lee J Martin
    Department of Pathology, Division of Neuropathology, and the Pathobiology Graduate Program, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 2196, USA
    J Bioenerg Biomembr 43:569-79. 2011
  7. pmc Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis
    Lee J Martin
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205 2196, USA
    Mol Neurobiol 45:30-42. 2012
  8. pmc Generation and characterization of transgenic mice expressing mitochondrial targeted red fluorescent protein selectively in neurons: modeling mitochondriopathy in excitotoxicity and amyotrophic lateral sclerosis
    Yi Wang
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, MD 21205, USA
    Mol Neurodegener 6:75. 2011
  9. pmc Motoneuron subtypes show specificity in glycine receptor channel abnormalities in a transgenic mouse model of amyotrophic lateral sclerosis
    Qing Chang
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Channels (Austin) 5:299-303. 2011
  10. pmc Glycine receptor channels in spinal motoneurons are abnormal in a transgenic mouse model of amyotrophic lateral sclerosis
    Qing Chang
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurosci 31:2815-27. 2011

Scientific Experts

  • Lee Martin
  • Yi Wang
  • Qing Chang
  • SANIYA FAYZULLINA
  • Barry Gertz
  • Margaret Wong
  • Barry A Chestnut
  • Kevin Chen
  • Ann Price
  • Catherine Lesuisse
  • Frances J Northington

Detail Information

Publications15

  1. pmc Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA)
    SANIYA FAYZULLINA
    Division of Neuropathology, Department of Pathology, and the Pathobiology Graduate Program, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
    PLoS ONE 9:e93329. 2014
    ..Overall, this work identifies DNA damage and cell death in skeletal muscle as therapeutic targets for SMA. ..
  2. pmc Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: a new target of disease mechanisms
    Lee J Martin
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD, 21205 2196, USA
    Neurotherapeutics 10:722-33. 2013
    ..Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS pathogenesis that could be relevant to new disease target identification and therapies for ALS. ..
  3. pmc Biology of mitochondria in neurodegenerative diseases
    Lee J Martin
    Division of Neuropathology, Department of Pathology, The Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Prog Mol Biol Transl Sci 107:355-415. 2012
    ..This chapter reviews several aspects of mitochondrial biology and how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in AD, PD, and ALS...
  4. pmc Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice
    Barry Gertz
    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 2196, USA
    J Neuropathol Exp Neurol 71:162-77. 2012
    ....
  5. pmc Epigenetic regulation of motor neuron cell death through DNA methylation
    Barry A Chestnut
    Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 2196, USA
    J Neurosci 31:16619-36. 2011
    ..Thus, motor neurons can engage epigenetic mechanisms to drive apoptosis, involving Dnmt upregulation and increased DNA methylation. These cellular mechanisms could be relevant to human ALS pathobiology and disease treatment...
  6. pmc Mitochondrial pathobiology in ALS
    Lee J Martin
    Department of Pathology, Division of Neuropathology, and the Pathobiology Graduate Program, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 2196, USA
    J Bioenerg Biomembr 43:569-79. 2011
    ..This paper reviews how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in ALS...
  7. pmc Inhibitory synaptic regulation of motoneurons: a new target of disease mechanisms in amyotrophic lateral sclerosis
    Lee J Martin
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205 2196, USA
    Mol Neurobiol 45:30-42. 2012
    ..Abnormal synaptic inhibition resulting from dysfunction of interneurons and motoneuron GlyRs is a new direction for unveiling mechanisms of ALS pathogenesis that could be relevant to new therapies for ALS...
  8. pmc Generation and characterization of transgenic mice expressing mitochondrial targeted red fluorescent protein selectively in neurons: modeling mitochondriopathy in excitotoxicity and amyotrophic lateral sclerosis
    Yi Wang
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, MD 21205, USA
    Mol Neurodegener 6:75. 2011
    ....
  9. pmc Motoneuron subtypes show specificity in glycine receptor channel abnormalities in a transgenic mouse model of amyotrophic lateral sclerosis
    Qing Chang
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Channels (Austin) 5:299-303. 2011
    ..These results indicate that GlyR deficiency early in the disease process of ALS is specific for large alpha motoneurons...
  10. pmc Glycine receptor channels in spinal motoneurons are abnormal in a transgenic mouse model of amyotrophic lateral sclerosis
    Qing Chang
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurosci 31:2815-27. 2011
    ..Our study suggests that selective alterations in GlyR function contribute to inhibitory insufficiency in motoneurons early in the disease process of ALS...
  11. pmc Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis
    Lee J Martin
    Johns Hopkins University School of Medicine, Departments of Pathology and Neuroscience, Baltimore, MD 21205 2196, USA
    IDrugs 13:568-80. 2010
    ..It has been granted orphan drug status for the treatment of ALS in the US and for the treatment of spinal muscular atrophy in the EU. Phase II/III clinical trials are in progress in Europe...
  12. ncbi Mitochondrial pathobiology in Parkinson's disease and amyotrophic lateral sclerosis
    Lee J Martin
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    J Alzheimers Dis 20:S335-56. 2010
    ..This review will present how mitochondrial pathobiology might contribute to neurodegeneration in PD and ALS and could serve as a target for drug therapy...
  13. pmc Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice
    Kevin Chen
    Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MA 21205 2196, USA
    Brain Struct Funct 214:219-34. 2010
    ..This work identifies two new potential early mechanisms for MN degeneration in mouse ALS involving iNOS at MN mitochondria and Schwann cells and suggests that therapies targeting iNOS might be beneficial in treating human ALS...
  14. pmc The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis therapy
    Lee J Martin
    Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 2196, USA
    Biochim Biophys Acta 1802:186-97. 2010
    ..Thus, attention should be directed to the mPTP as a rational target for the development of drugs designed to treat ALS...