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

Fayzullina, Saniya; Martin, Lee J.

doi:10.1371/journal.pone.0093329

Cited by 38 publications

(40 citation statements)

References 87 publications

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“…This possibility has been suggested by SMA models of SMN point mutations that recapitulate motor neuron degeneration in the absence of defects in snRNP assembly (69). Alternatively, there likely is less prominent pathology in other cell types (70).…”

Section: Discussionmentioning

confidence: 95%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

107

111

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Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.

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Section: Discussionmentioning

confidence: 95%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

107

111

View full text Add to dashboard Cite

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“…We have found that skeletal muscle DNA damage accumulation precedes motor neuron DNA damage in SMA mice (14). Therefore, we investigated the capacity of satellite cellderived differentiated mouse skeletal muscle cells to detect and repair DNA damage and tested the hypothesis that DDR and DNA repair capacities are defective in SMA mouse skeletal muscle cells.…”

Section: Introductionmentioning

confidence: 99%

“…A mouse model of infantile spinal muscular atrophy (SMA) with skeletal muscle degeneration and neonatal lethality develops prominent DNA damage accumulation and apoptosis in skeletal muscle, but no activation of p53 and selected other DDR genes above baseline (14). SMA is caused by mutations in the human Survival of motor neuron-1 (Smn1) gene (15).…”

Section: Introductionmentioning

confidence: 99%

“…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). Using these mice (14), we first characterized a myocyte culture model of SMA cells by monitoring expression of differentiation markers, myocyte morphology, and the ability of differentiated myotubes to cluster nicotinic acetylcholine receptors (AChRs) in response to agrin (26,27).…”

Section: Introductionmentioning

confidence: 99%

“…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). Using these mice (14), we first characterized a myocyte culture model of SMA cells by monitoring expression of differentiation markers, myocyte morphology, and the ability of differentiated myotubes to cluster nicotinic acetylcholine receptors (AChRs) in response to agrin (26,27). (Here, we use the term "myocyte" to refer to all muscle-derived cells, including muscle satellite cells and differentiated myotubes).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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Basal forebrain magnocellular cholinergic systems are damaged in mice following neonatal hypoxia‐ischemia

Northington¹,

Kratimenos

Turnbill³

et al. 2021

J of Comparative Neurology

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Neonatal hypoxic‐ischemic encephalopathy (HIE) causes lifelong neurologic disability. Despite the use of therapeutic hypothermia, memory deficits and executive functions remain severely affected. Cholinergic neurotransmission from the basal forebrain to neocortex and hippocampus is central to higher cortical functions. We examined the basal forebrain by light microscopy and reported loss of choline acetyltransferase‐positive (ChAT)+ neurons, at postnatal day (P) 40, in the ipsilateral medial septal nucleus (MSN) after neonatal hypoxia‐ischemia (HI) in mice. There was no loss of ChAT+ neurons in the ipsilateral nucleus basalis of Meynert (nbM) and striatum. Ipsilateral striatal and nbM ChAT+ neurons were abnormal with altered immunoreactivity for ChAT, shrunken and crenated somas, and dysmorphic appearing dendrites. Using confocal images with 3D reconstruction, nbM ChAT+ dendrites in HI mice were shorter than sham (p = .0001). Loss of ChAT+ neurons in the MSN directly correlated with loss of ipsilateral hippocampal area. In the nbM and striatum, percentage of abnormal ChAT+ neurons correlated with loss of ipsilateral cerebral cortical and striatal area, respectively. Acetylcholinesterase (AChE) activity increased in adjacent ipsilateral cerebral cortex and hippocampus and the increase was linearly related to loss of cortical and hippocampal area. Numbers and size of cathepsin D+ lysosomes increased in large neurons in the ipsilateral nbM. After neonatal HI, abnormalities were found throughout the major cholinergic systems in relationship to amount of forebrain area loss. There was also an upregulation of cathepsin D+ particles within the nbM. Cholinergic neuropathology may underlie the permanent dysfunction in learning, memory, and executive function after neonatal brain injury.

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

Cited by 38 publications

References 87 publications

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

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

Basal forebrain magnocellular cholinergic systems are damaged in mice following neonatal hypoxia‐ischemia

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