Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).
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PMID:The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. 1158 85

We studied 15 patients, from 10 families, who presented with severe spastic paralysis with an infantile onset and an ascending progression. Spastic paraplegia began during the first 2 years of life and extended to upper limbs within the next few years. During the first decade of life, the disease progressed to tetraplegia, anarthria, dysphagia, and slow eye movements. Overall, the disease was compatible with long survival. Signs of lower motor-neuron involvement were never observed, whereas motor-evoked potentials and magnetic resonance imaging demonstrated a primitive, pure degeneration of the upper motor neurons. Genotyping and linkage analyses demonstrated that this infantile-onset ascending hereditary spastic paralysis (IAHSP) is allelic to the condition previously reported as juvenile amyotrophic lateral sclerosis at the ALS2 locus on chromosome 2q33-35 (LOD score 6.66 at recombination fraction 0). We analyzed ALS2, recently found mutated in consanguineous Arabic families presenting either an ALS2 phenotype or juvenile-onset primary lateral sclerosis (JPLS), as a candidate gene. In 4 of the 10 families, we found abnormalities: three deletions and one splice-site mutation. All the mutations lead to a truncated alsin protein. In one case, the mutation affected both the short and the long alsin transcript. In the six remaining families, absence of cDNA ALS2 mutations suggests either mutations in regulatory ALS2 regions or genetic heterogeneity, as already reported in JPLS. Alsin mutations are responsible for a primitive, retrograde degeneration of the upper motor neurons of the pyramidal tracts, leading to a clinical continuum from infantile (IAHSP) to juvenile forms with (ALS2) or without (JPLS) lower motor-neuron involvement. Further analyses will determine whether other hereditary disorders with primitive involvement of the central motor pathways, as pure forms of spastic paraplegia, could be due to alsin dysfunction.
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PMID:Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. 1214 48

Eight mutations in the ALS2 gene have been described as causing autosomal-recessive juvenile-onset forms of the motor neuron diseases amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. All mutations are small deletions that are predicted to result in a frameshift and premature truncation of the alsin protein. Here we describe a ninth ALS2 mutation, in two siblings affected by infantile-onset ascending spastic paraplegia with bulbar involvement. This mutation is predicted to result in the substitution of an amino acid by a stop codon, and thus is the first nonsense mutation detected in this gene. It is probable that full-length alsin is required for the proper development and/or functioning of upper motor neurons.
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PMID:The first nonsense mutation in alsin results in a homogeneous phenotype of infantile-onset ascending spastic paralysis with bulbar involvement in two siblings. 1291 35

It is estimated that between 10-20% of amyotrophic lateral sclerosis (ALS) is familial and these cases encompass recessive and dominant modes of inheritance. So far, mutations in three genes, superoxide dismutase 1 (SOD1), the p150 subunit of dynactin (DCTN1), and alsin have been shown to be directly causal for motor neuron degeneration in humans. However, clearly the disorder is genetically heterogeneous and other causal genes remain to be found that explain the vast majority of familial ALS cases. Human genetics can be problematical in that it is difficult to detect linkage in disorders in which multiple loci give similar phenotypes and where families are often small. In addition, the vertical collection of generations is often not possible with late onset disorders. An excellent genetic model of humans is provided by the mouse. We can use mouse models of neurodegeneration to find new genes in the human population. These models are not exact replicas of the human condition, but are the mouse equivalent and are incredibly valuable resources for highlighting genes and biochemical pathways disrupted in ALS and other diseases. In addition mouse models give us access to both control and affected tissues, at all stages of development and disease, thus greatly facilitating our understanding of pathogenesis. They also provide us with model systems for testing new therapies. Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles (Loa).
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PMID:Paradigms for the identification of new genes in motor neuron degeneration. 1475 59

Mutation of the ALS2 gene encoding alsin is linked to the onset of autosomal recessive motor neuron diseases, including juvenile-onset amyotrophic lateral sclerosis (ALS). Alsin long form (LF) belongs to the family of the guanine nucleotide exchanging factor (GEF) for small GTPases. Expression of alsin LF, but not alsin short form, protected motor neuronal cells from toxicity induced by mutants of the Cu/Zn-superoxide dismutase (SOD1) gene, which cause autosomal dominant ALS. In contrast, expression of alsin did not suppress neurotoxicity by other neurodegenerative insults such as Alzheimer's disease-related genes. Deletion analysis of alsin LF demonstrated that the RhoGEF domain is essential for alsin-mediated neuroprotection. Furthermore, we found that alsin LF bound to SOD1 mutants, but not to wtSOD1, via the RhoGEF domain. Such functional and physical interaction between two ALS-related genes will become a promising clue to clarify the pathogenesis of ALS and other motor neuron diseases.
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PMID:Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants. 1497 Feb 33

ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs. To gain insight into the overall function of alsin and to begin to evaluate its role in motor neuron maintenance, we examined the subcellular localization of alsin and the biochemical activities associated with its individual subdomains. We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange activity. In addition, alsin interacted specifically with and acted as a guanine nucleotide exchange factor for Rac1. Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures. Many of these membrane structures also contained Rab5 or Rac1. Upon overexpression of full-length alsin, the overexpressed material was largely cytosolic, indicating that the association with membrane structures could be saturated. We also found that alsin was present in membrane ruffles and lamellipodia. These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.
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PMID:Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. 1503 76

The Golgi apparatus of motor neurons (GA) is fragmented in sporadic amyotrophic lateral sclerosis (ALS), in familial ALS with SOD1 mutations, and in mice that express SOD1G93A of familial ALS, in which it was detected months before paralysis. In paralyzed transgenic mice expressing SOD1G93A or SOD1G85R, mutant proteins aggregated not only in the cytoplasm of motor neurons, but also in astrocytes and oligodendrocytes. Furthermore, aggregation of the G85R protein damaged astrocytes and was associated with rapidly progressing disease. In order to gain insight into the functional state of the fragmented GA, we examined the effects of S0D1 mutants G93A and G85R in Chinese Hamster Ovary Cells (CHO). In contrast to cells expressing the wt and G93A, the G85R expressers had no SOD1 activity. However, cells expressing both mutants, and to a lesser degree the wt, showed decreased survival, fragmentation of the GA, and dysfunction of the secretory pathway, which was assessed by measuring the amount of cell surface co-expressed CD4, a glycoprotein processed through the GA. The G93A and wt proteins were partially recovered in detergent insoluble fractions; while the recovery of G85R was minimal. Both mutants showed equal reductions of cell survival and function of the secretory pathway, in comparison to the wt and cells expressing mutant alsin, a protein found in rare cases of fALS. These results are consistent with the conclusion that the two SOD1 mutants, by an unknown mechanism, promote the dispersion of the GA and the dysfunction of the secretory pathway. This and other in vitro models of mutant SOD1 toxicity may prove useful in the elucidation of pathogenetic mechanisms.
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PMID:Disruption of the structure of the Golgi apparatus and the function of the secretory pathway by mutants G93A and G85R of Cu, Zn superoxide dismutase (SOD1) of familial amyotrophic lateral sclerosis. 1505 Apr 37

Amyotrophic lateral sclerosis is a progressive neurological disorder. It is characterised by selective motor-neuron degeneration in the cortex, brainstem, and spinal cord. Consequently, patients suffer from muscle weakness and usually die within 3-5 years after diagnosis from respiratory insufficiency. About 5-10% of the patients have a family history of ALS, the remaining are classified as sporadic ALS. There is only limited information about genetic susceptibility factors in sporadic ALS. Some patients with familial ALS have mutations in the gene encoding for copper/zinc superoxide dismutase, a protein involved in scavenging superoxide radicals. This results in a toxic gain of function. Mutations in the gene coding for alsin, ALS2, have been shown to be responsible for an autosomal recessive form of juvenile ALS.
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PMID:[From gene to disease: amyotrophic lateral sclerosis]. 1555 56

Mutations in the ALS2 gene, which encodes alsin, cause autosomal recessive juvenile-onset amyotrophic lateral sclerosis (ALS2) and related conditions. Using both a novel monoclonal antibody and LacZ knock-in mice, we demonstrate that alsin is widely expressed in neurons of the CNS, including the cortex, brain stem and motor neurons of the spinal cord. Interestingly, the highest levels of alsin are found in the molecular layer of the cerebellum, a brain region not previously implicated in ALS2. During development, alsin is expressed by day E9.5, but CNS expression does not become predominant until early postnatal life. At the subcellular level, alsin is tightly associated with endosomal membranes and is likely to be part of a large protein complex that may include the actin cytoskeleton. ALS2 is present in primates, rodents, fish and flies, but not in the nematode worm or yeast, and is more highly conserved than expected among mammals. Additionally, the product of a second, widely expressed gene, ALS2 C-terminal like (ALS2CL), may subserve or modulate some of the functions of alsin as an activator of Rab and Rho GTPases.
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PMID:Cross-species characterization of the ALS2 gene and analysis of its pattern of expression in development and adulthood. 1568 53

There is growing evidence for the involvement of cytoskeletal defects in the pathogenesis of motor neuron disease and especially in components of the microtubule-based transport system. Here we will review our recent work aiming to elucidate the role of peripherin in amyotrophic lateral sclerosis (ALS) and to address the mechanism of disease caused by deletions in the ALS2 gene that cause recessive forms of juvenile ALS and primary lateral sclerosis (PLS). Peripherin is an intermediate filament protein detected in spheroids, a hallmark of ALS, and increased levels of peripherin mRNA have been found in some ALS cases. Our transgenic mouse and cell culture studies support the view of a peripherin involvement in ALS. However, a gene knockout approach demonstrated that peripherin is not a key contributor of motor neuron disease caused by mutant superoxide dismutase linked to familial ALS. A recent breakthrough in the field of ALS came with the discovery of frameshift deletions in the ALS2 gene coding for Alsin. Our transfection experiments in cultured cells suggest that Alsin is a cytoskeletal protein with dual endosomal and centrosomal localizations. We have generated a mouse knockout for Alsin that develops progressive motor dysfunction during ageing. Thus, it is anticipated that this mouse model will be useful to investigate the pathogenic pathways linked to Alsin gene mutations.
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PMID:Cytoskeletal defects in amyotrophic lateral sclerosis (motor neuron disease). 1577 54


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