Amyotrophic leteral sclerosis: Part 2. Etiopathogenesis

Tandan, Rup; Bradley, Walter G.

doi:10.1002/ana.410180402

Cited by 139 publications

(33 citation statements)

References 136 publications

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“…Large lumbar motor neurons with a cell body area of ≥450 μm 2 were quantified using the neuronal marker NeuN. Thus, only the large α-motor neurons most vulnerable to cell death in ALS (2,38,39) were quantified, and the γ-type motor neurons that are resistant to the disease were excluded. In SOD1 G93A littermates at the presymptomatic stage, no motor neuron cell death was detected, but by the time of disease onset, only 45.8% of motor neurons had survived, with 19.3% of motor neurons surviving at 120 d of age ( Fig.…”

Section: Atf3 Promotesmentioning

confidence: 99%

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

Seijffers

Zhang

Matthews

et al. 2014

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

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Significance This study reports on the beneficial effects of forcing high expression of the transcription factor activating transcription factor 3 (ATF3) in ALS. ALS is a noncurable adult-onset disease that attacks motor neurons, resulting in paralysis and death. ATF3 overexpression in motor neurons in an ALS mouse model modifies gene expression and drives the neurons into a prosurvival and proregenerative state, increasing motor neuron survival and maintaining axonal connection with muscle by promoting axonal sprouting. ATF3 overexpression results in markedly improved muscle strength and function and delayed disease onset but only slightly increased lifespan. Molecular mechanisms that promote axonal sprouting could substantially improve quality of life in ALS, although additional approaches will be required to overcome progressive motor neuron deterioration.

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Section: Atf3 Promotesmentioning

confidence: 99%

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

Seijffers

Zhang

Matthews

et al. 2014

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

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“…genome-wide association study ͉ single nucleotide polymorphism A myotrophic lateral sclerosis (ALS) is an age-dependent, degenerative disorder of motor neurons (1) that typically develops in the 6th decade and is uniformly fatal, usually within 5 years (2). Approximately 10% of ALS cases are dominantly inherited (3); 20% of these are caused by mutations in the gene encoding copper/zinc superoxide dismutase 1 (SOD1) (4); mutations in the TARDBP gene (5,6) account for Ϸ5% of cases.…”

mentioning

confidence: 99%

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Landers

Melki

Meininger

et al. 2009

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

167

110

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Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genomewide significant result (P ‫؍‬ 1.84 ؋ 10 ؊8 ) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.genome-wide association study ͉ single nucleotide polymorphism A myotrophic lateral sclerosis (ALS) is an age-dependent, degenerative disorder of motor neurons (1) that typically develops in the 6th decade and is uniformly fatal, usually within 5 years (2). Approximately 10% of ALS cases are dominantly inherited (3); 20% of these are caused by mutations in the gene encoding copper/zinc superoxide dismutase 1 (SOD1) (4); mutations in the TARDBP gene (5, 6) account for Ϸ5% of cases. Rare familial cases arise from mutations in genes encoding the vesicle-associated membrane associated protein B (7), alsin (a RAB5-guanine nucleotide exchange factor) (8, 9), senataxin (10) or dynactin (11). Recently, we reported that Ϸ5% of familial ALS cases are due to mutations in the FUS/TLS gene (12, 13) whose product binds DNA and RNA, as does TARDBP. The cause of sporadic ALS is thought to be multifactorial, with environmental, infectious and genetic etiologies. Reported associations with variants in diverse genes (14-25) have proven difficult to replicate. Advances in the technology for large-scale genotyping of single nucleotide polymorphisms (SNPs) have facilitated unbiased, genome-wide association studies. Examples include the identification of IL2RA and IL7RA variants as risk factors for multiple sclerosis (26-28) and the recent reports of 6 new gene regions associated with type 2 diabetes (29)(30)(31)(32)(33)(34)(35). To test the hypothesis that commonly occurring genetic

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“…The existence of risk factors for spo radic ALS has been discussed. The following risk factors have been considered: skeletal trauma, fractures, surgery, hard work and in tense athletic activity [16,17]. Some authors suggested that exposure to heavy metals was a significant factor, but others disagreed [18].…”

Section: Introductionmentioning

confidence: 99%

Epidemiological Survey of Amyotrophic Lateral Sclerosis in the Province of Reggio Emilia, Italy: Influence of Environmental Exposure to Lead

et al. 1996

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We carried out a retrospective incidence, prevalence and mortality survey of amyotrophic lateral sclerosis (ALS) in the province of Reggio Emilia, northern Italy. Based on 79 patients, the mean incidence per year for the period 1980 through 1992 was 1.5 cases per 100,000. On December 31st, 1992, the prevalence rate was 5.4 per 100,000. In the 10-year period of 1983–1992 the average mortality rate was 1.3 per 100,000 per year. The average age at onset was 61.3 ± 10.2, the average survival period thereafter was 26.3 months ± 17.7; 27.3 ± 17.6 for classic ALS, 19.5 ±8.4 for progressive bulbar palsy and 36.3 ±41.4 for pseudopolyneuritic ALS. The incidence rate, recorded in public health district No. 12, an area with documented lead pollution since the 1970s, was standardized to the sex and age of the population of the province. Its incidence and prevalence rate were comparable to the rates found in the remaining area of the province.

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Amyotrophic leteral sclerosis: Part 2. Etiopathogenesis

Cited by 139 publications

References 136 publications

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Epidemiological Survey of Amyotrophic Lateral Sclerosis in the Province of Reggio Emilia, Italy: Influence of Environmental Exposure to Lead

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