Spinal Muscular Atrophy

Vitte, Jérémie; Attali, Ruben; Warwar, Nasim; Gurt, Irena; Melki, Judith

doi:10.1007/978-90-481-2813-6_16

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…Humans have a related gene, Smn2, which is a near-duplicate of Smn1; this gene influences morbidity in infants without Smn1 in ways related to copy number and the production of some full-length SMN from Smn2 gene transcripts (15,23,24). Human Smn2 has thus been used as a tool to overcome embryonic lethality of the homozygous Smn1 null mutation in mice although these mice still die early postnatally (14,25).…”

Section: Introductionmentioning

confidence: 99%

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

Fayzullina

Martin

2016

J Neuropathol Exp Neurol

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We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by c-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After c-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phosphop53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA.

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Section: Introductionmentioning

confidence: 99%

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

Fayzullina

Martin

2016

J Neuropathol Exp Neurol

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“…Type II SMA patients live past 2 years of age and can sit but are never able to walk. Type III SMA patients experience onset of symptoms after 18 months of age, and are able to walk but have muscle weakness and decreased endurance [3], [5]–[9]. SMN1 mutations result in reduced levels of full-length SMN protein.…”

Section: Introductionmentioning

confidence: 99%

Skeletal Muscle DNA Damage Precedes Spinal Motor Neuron DNA Damage in a Mouse Model of Spinal Muscular Atrophy (SMA)

Fayzullina¹,

Martin²

2014

PLoS ONE

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Spinal Muscular Atrophy (SMA) is a hereditary childhood disease that causes paralysis by progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. The mechanisms by which lack of SMN causes SMA pathology are not known, making it very difficult to develop effective therapies. We investigated whether DNA damage is a perinatal pathological event in SMA, and whether DNA damage and cell death first occur in skeletal muscle or spinal cord of SMA mice. We used a mouse model of severe SMA to ascertain the extent of cell death and DNA damage throughout the body of prenatal and newborn mice. SMA mice at birth (postnatal day 0) exhibited internucleosomal fragmentation in genomic DNA from hindlimb skeletal muscle, but not in genomic DNA from spinal cord. SMA mice at postnatal day 5, compared with littermate controls, exhibited increased apoptotic cell death profiles in skeletal muscle, by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and electron microscopy. SMA mice had no increased cell death, no loss of choline acetyl transferase (ChAT)-positive motor neurons, and no overt pathology in the ventral horn of the spinal cord. At embryonic days 13 and 15.5, SMA mice did not exhibit statistically significant increases in cell death profiles in spinal cord or skeletal muscle. Motor neuron numbers in the ventral horn, as identified by ChAT immunoreactivity, were comparable in SMA mice and control littermates at embryonic day 15.5 and postnatal day 5. These observations demonstrate that in SMA, disease in skeletal muscle emerges before pathology in spinal cord, including loss of motor neurons. Overall, this work identifies DNA damage and cell death in skeletal muscle as therapeutic targets for SMA.

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Early onset (childhood) monogenic neuropathies

Landrieu

Baets

2013

Handbook of Clinical Neurology

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Spinal Muscular Atrophy

Cited by 3 publications

References 52 publications

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

Skeletal Muscle DNA Damage Precedes Spinal Motor Neuron DNA Damage in a Mouse Model of Spinal Muscular Atrophy (SMA)

Early onset (childhood) monogenic neuropathies

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