Skeletal Muscle in Amyotrophic Lateral Sclerosis: Emerging Concepts and Therapeutic Implications

Abmayr, Simone; Weydt, Patrick

doi:10.1016/j.pmr.2005.08.013

Cited by 5 publications

(2 citation statements)

References 35 publications

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“…Muscle involvement in the pathogenesis and progression of ALS has long been debated (Abmayr and Weydt, 2005), and VCP -associated disease may represent an instance in which muscle and nerve are simultaneously affected, thus offering an opportunity to dissect this relationship. At the very least, our data widen the clinical symptomatology associated with VCP mutations to include an ALS phenotype, and suggest that familial ALS patients should be monitored for features of IBM and osteoclast dysfunction (for example, by screening for elevated serum alkaline phosphatase).…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Johnson

Mandrioli

Benatar

et al. 2010

Neuron

1,107

680

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Summary Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget’s disease and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically-proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ~1–2% of familial ALS, and represent the first evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.

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Section: Discussionmentioning

confidence: 99%

Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Johnson

Mandrioli

Benatar

et al. 2010

Neuron

1,107

680

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“…However, weight loss in SOD1 mice might result not only from muscle wasting attributed to muscle denervation, but also from malnutrition due to dysphagia, developmental abnormalities and other unrelated reasons; thus body weight is an unspecific parameter to monitor disease in SOD1 mice. Recently, some authors thought that ALS might be a multisystem disorder and that skeletal muscle was more autonomously involved, which resulted in significant weight loss in ALS (16,17). Thus, body weighing might be a simple and specific method for assessing the therapeutic efficacy of novel interventions targeting muscle tissue.…”

Section: Discussionmentioning

confidence: 99%

A method comparison in monitoring disease progression of G93A mouse model of ALS

Zhou

Zhao²,

Zhang

et al. 2007

Amyotrophic Lateral Sclerosis

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Our aim was to find an optimal method for monitoring disease progression and assessing the effectiveness of new agents in SOD1 mice. We compared six testing methods including clinical grading, weighing, hanging wire test, rotarod test, motor neuron counting and motor unit number estimation (MUNE) in SOD1 mice and control animals. The six methods were all able to differentiate between control animals and SOD1 transgenic mice at some time points; of them motor neuron counting, weighing and MUNE could detect abnormalities in presymptomatic stage in SOD1 mice; The number of functional motor units precisely correlated with motor neuron counts (r = 0.894, p<0.01). We concluded that MUNE is the better testing measure for monitoring disease and evaluating pharmacological therapies in SOD1 mice, which not only can reflect a meaningful biological effect of the agents used, but also is a sensitive, accurate and practical method.

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Amino Acids as biomarkers in the SOD1G93A mouse model of ALS

Bame

Grier

Needleman

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The development of therapies for Amyotrophic Lateral Sclerosis (ALS) has been hindered by the lack of biomarkers for both identifying early disease and for monitoring the effectiveness of drugs. The identification of ALS biomarkers in presymptomatic individuals might also provide clues to the earliest biochemical correlates of the disease. Previous attempts to use plasma metabolites as biomarkers have led to contradictory results, presumably because of heterogeneity in both the underlying genetics and the disease stage in the clinical population. To eliminate these two sources of heterogeneity we have characterized plasma amino acids and other metabolites in the SOD1(G93A) transgenic mouse model for ALS. Presymptomatic SOD1(G93A) mice have significant differences in concentrations of several plasma metabolites compared to wild type animals, most notably in the concentrations of aspartate, cystine/cysteine, and phosphoethanolamine, and in changes indicative of methylation defects. There are significant changes in amino acid compositions between 50 and 70days of age in both the SOD1(G93A) and wild type mice, and several of the age-related and disease-related differences in metabolite concentration were also gender-specific. Many of the SOD1(G93A)-related differences could be altered by treatment of mice with methionine sulfoximine, which extends the lifespan of this mouse, inhibits glutamine synthetase, and modifies brain methylation reactions. These studies show that assaying plasma metabolites can effectively distinguish transgenic mice from wild type, suggesting that one or more plasma metabolites might be useful biomarkers for the disease in humans, especially if genetic and longitudinal analysis is used to reduce population heterogeneity.

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Skeletal Muscle in Amyotrophic Lateral Sclerosis: Emerging Concepts and Therapeutic Implications

Cited by 5 publications

References 35 publications

Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

A method comparison in monitoring disease progression of G93A mouse model of ALS

Amino Acids as biomarkers in the SOD1G93A mouse model of ALS

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