Genetics of sporadic amyotrophic lateral sclerosis

Schymick, Jennifer C.; Talbot, Kevin; Traynor, Bryan J.

doi:10.1093/hmg/ddm215

Cited by 151 publications

(100 citation statements)

References 82 publications

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“…Approximately 5 to 10% of ALS cases are familial; the rest appear to be sporadic (1)(2)(3). Mutations in SOD1 account for Ϸ20% of the familial ALS cases and 1 to 5% of the cases of sporadic ALS (1-4); Ͼ120 different SOD1 mutations have been identified in ALS patients (http://alsod.iop.kcl.ac.uk/Als/index.aspx).…”

mentioning

confidence: 99%

Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis

Awano¹,

Johnson²,

Wade

et al. 2009

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

225

343

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Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.

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confidence: 99%

Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis

Awano¹,

Johnson²,

Wade

et al. 2009

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

225

343

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“…The molecular pathogenesis of ALS is not understood [5,[13][14][15], contributing to the lack of appropriate and legitimate disease target identification, and effective mechanism-based therapies to treat this fatal disease. Many theories have implicated perturbations in neurotrophin availability, axonal transport, glutamate receptors and transporters, protein quality control, mitochondria, bioenergetics, antioxidant status, apoptosis, inflammation, and autoimmunity in the mechanisms of ALS pathogenesis [5,6,16].…”

Section: Introductionmentioning

confidence: 99%

Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

Martin

Wong

2013

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. 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.

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“…FALS is caused by mutations in some genes, such as those coding for SOD1, FUS RNA binding protein, TAR DNA binding protein, vesicleassociated membrane protein B, valosin-containing protein, optineurin, alsin, senataxin, spatascin, angiogenin, or ubiquilin-2 [24,26]. Some of these gene mutations have also been found in SALS patients [28,29].…”

Section: Introductionmentioning

confidence: 99%