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 is the most common motor neuron disease and is still incurable. The mechanisms leading to the selective motor neuron vulnerability are still not known. The interplay between motor neurons and astrocytes is crucial in the outcome of the disease. We show that mutant copper-zinc superoxide dismutase (SOD1) overexpression in primary astrocyte cultures is associated with decreased levels of proteins involved in secretory pathways. This is linked to a general reduction of total secreted proteins, except for specific enrichment in a number of proteins in the media, such as mutant SOD1 and valosin-containing protein (VCP)/p97. Because there was also an increase in exosome release, we can deduce that astrocytes expressing mutant SOD1 activate unconventional secretory pathways, possibly as a protective mechanism. This may help limit the formation of intracellular aggregates and overcome mutant SOD1 toxicity. We also found that astrocyte-derived exosomes efficiently transfer mutant SOD1 to spinal neurons and induce selective motor neuron death. We conclude that the expression of mutant SOD1 has a substantial impact on astrocyte protein secretion pathways, contributing to motor neuron pathology and disease spread.
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PMID:Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. 2359 92

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. Varied clinical features caused by VCP mutations have been reported: these clinical phenotypes include distal myopathy, frontotemporal dementia and amyotrophic lateral sclerosis. We report a 49-year-old woman with 3-year history of progressive proximal limb muscle weakness. Family history was notable for her father with motor neuron disease and an elder brother with a myopathy involving tibialis anterior and quadriceps. Neurological examinations showed proximal muscle atrophy, especially severe atrophy of paravertebral muscles, right-dominant scapular winging, bilateral pyramidal signs and hyperreflexia. Serum CK level was normal and EMG showed chronic neurogenic changes. Muscle imaging (CT) showed adipose tissue replacement of paravertebral muscles and right serratus anterior, and marked atrophy of bilateral trapezius and vastus intermedius muscles. Her lumbar spine X-ray showed an osteosclerotic change in the vertebral body, where an increased uptake of Tc99m was also observed in bone scintigraphy. Although brain MRI was normal, neuropsychological examination showed a mild attention deficit with cognitive impairment. A muscle biopsy specimen revealed scattered fibers with rimmed vacuoles. These findings prompted us to analyze a mutation in the VCP gene. Genomic sequencing of all exons of the gene showed a heterozygous missense mutation in exon 5 (c.1315G>C; p.Ala439Pro).
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PMID:[A case of inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) showing clinical features of motor neuron disease]. 2378 24

Stress granules and P bodies are conserved cytoplasmic aggregates of nontranslating messenger ribonucleoprotein complexes (mRNPs) implicated in the regulation of mRNA translation and decay and are related to RNP granules in embryos, neurons, and pathological inclusions in some degenerative diseases. Using baker's yeast, 125 genes were identified in a genetic screen that affected the dynamics of P bodies and/or stress granules. Analyses of such mutants, including CDC48 alleles, provide evidence that stress granules can be targeted to the vacuole by autophagy, in a process termed granulophagy. Moreover, stress granule clearance in mammalian cells is reduced by inhibition of autophagy or by depletion or pathogenic mutations in valosin-containing protein (VCP), the human ortholog of CDC48. Because mutations in VCP predispose humans to amyotrophic lateral sclerosis, frontotemporal lobar degeneration, inclusion body myopathy, and multisystem proteinopathy, this work suggests that autophagic clearance of stress granule related and pathogenic RNP granules that arise in degenerative diseases may be important in reducing their pathology.
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PMID:Eukaryotic stress granules are cleared by autophagy and Cdc48/VCP function. 2379 Nov 77

FIG4 is a phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. Mutations of FIG4 lead to the development of Charcot-Marie-Tooth disease type 4J and amyotrophic lateral sclerosis (ALS). Moreover, ALS-associated proteins (transactivation response DNA protein 43 (TDP-43), fused in sarcoma (FUS), optineurin, ubiquilin-2, charged mutivesicular body protein 2b (CHMP2B) and valosin-containing protein) are involved in inclusion body formation in several neurodegenerative diseases. Using immunohistochemistry, we examined the brains and spinal cords of patients with various neurodegenerative diseases, including sporadic TDP-43 proteinopathy (ALS and frontotemporal lobar degeneration). TDP-43 proteinopathy demonstrated no FIG4 immunoreactivity in neuronal inclusions. However, FIG4 immunoreactivity was present in Pick bodies in Pick's disease, Lewy bodies in Parkinson's disease and dementia with Lewy bodies, neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases, and Marinesco and Hirano bodies in aged control subjects. These findings suggest that FIG4 is not incorporated in TDP-43 inclusions and that it may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases.
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PMID:ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases. 2388 80

Breakthrough discoveries identifying common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have transformed our view of these disorders. They share unexpectedly similar signatures, including dysregulation in common molecular players including TDP-43, FUS/TLS, ubiquilin-2, VCP, and expanded hexanucleotide repeats within the C9ORF72 gene. Dysfunction in RNA processing and protein homeostasis is an emerging theme. We present the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
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PMID:Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. 2393 93

In the last years, new disease proteins and genes have been identified in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), leading to a dramatic shift in our understanding of the molecular mechanisms underlying both conditions. The vast majority of FTLD and ALS are characterized by the abnormal accumulation of TDP-43, including genetic forms associated with mutations in the genes C9ORF72, GRN, TARDBP and VCP. The overlap in pathology and of genetic factors, particularly C9ORF72 as common cause of ALS and FTLD, provides molecular evidence that both conditions represent a spectrum of diseases sharing similar pathomechanisms. Accumulation of the protein FUS defines another subset of FTLD and ALS. However, here some striking differences have been identified. All members of the FET family (FUS, EWS, TAF15) are co-accumulating with their nuclear import receptor Transportin in FTLD-FUS which is usually not associated with FUS mutations, whilst ALS-FUS is almost always associated with FUS mutations and reveals only FUS aggregates. Together with recent data demonstrating differences in the arginine methylation status of FUS in FTLD-FUS and ALS-FUS, these findings strongly imply at least partially distinct underlying disease mechanisms in these molecular subtypes of ALS and FTLD.
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PMID:Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: molecular similarities and differences. 2401 41

The last decade marked a turning point in the knowledge of frontotemporal lobar degenerations (FTLD). Major discoveries were made with the identification of TDP-43 and FUS, two novel key players in FTLD. The growing number of FTLD genes has considerably changed our clinical practice. The high intrafamilial variability of phenotypes underlines the necessity of a careful interview concerning the family history, regarding FTLD diseases, but also other neurodegenerative and extra-neurological disorders. Knowledge of the different genetic forms of FTLD and their associated phenotypes become essential to propose appropriate genetic diagnosis to the patients, and deliver accurate genetic counseling to their families. We propose an algorithm based on four criteria to help to pinpoint the genetic cause of FTLD: Presence of ALS in the patient or family; age at onset of FTLD; progranulin plasma level; and other disorders present in the patient or family. Presence of ALS is strongly indicative of a C9ORF72 expansion; a very early age at onset (<50 years), parkinsonism and oculomotor dysfunction are indicative of MAPT mutations; whereas hallucinations, CBDS and PNFA are indicative of PGRN mutations. A C9ORF72 repeat expansion should be searched for therefore in patients with FTLD-ALS, followed by sequencing of exon 6 of TARDBP gene in negative cases. Since C9ORF72 expansions are as frequent as PGRN mutations in patients with pure FTLD, both should be investigated, except in early familial FTLD (<50) where MAPT mutations should be searched for first. VCP, SQSTM1 and hnRNPA2B1 gene-sequencing could be proposed in patients or families presenting 'multisystem proteinopathy'. The genes currently identified explain 50-60% of familial forms of FTLD. The identification of new FTLD genes involved remains a major challenge to gain further insight into the pathology and even better clarify the classification of FTLD in the future.
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PMID:Genetics of frontotemporal lobar degeneration: an up-date and diagnosis algorithm. 2401 80

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting both upper and lower motor neurons. The prognosis for ALS is extremely poor, but there is a limited course of treatment with only one approved medication. A most striking recent discovery is that TDP-43 is identified as a key molecule that is associated with both sporadic and familial forms of ALS. TDP-43 is not only a pathological hallmark, but also a genetic cause for ALS. Subsequently, a number of ALS-causative genes have been found. Above all, the RNA-binding protein, such as FUS, TAF15, EWSR1 and hnRNPA1, have structural and functional similarities to TDP-43, and physiological functions of some molecules, including VCP, UBQLN2, OPTN, FIG4 and SQSTM1, are involved in a protein degradation system. These discoveries provide valuable insight into the pathogenesis of ALS, and open doors for developing an effective disease-modifying therapy.
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PMID:Amyotrophic lateral sclerosis: an update on recent genetic insights. 2408 47

Mutations in the sequestosome 1 gene (SQSTM1) have recently been identified in patients with amyotrophic lateral sclerosis, accounting for 1.11%-4.92% of familial ALS and 2.42%-4.37% of sporadic amyotrophic lateral sclerosis (SALS). The mutation spectrum of SQSTM1 in Chinese patients with SALS remains unknown. Three hundred and six patients with SALS from the Department of Neurology, West China Hospital of Sichuan University were recruited for this study. From the same region, 350 healthy individuals were recruited as a control group. The encoding regions of SQSTM1 were screened by direct sequencing. Three novel nonsynonymous mutations- p. I99L, p. D337E, and p. L341V-were identified in 3 patients with SALS, none of which were found in healthy controls. The male patient carrying mutation p. I99L presented limb symptom at age of 34 and died in 34 months. Two late-onset patients carrying D337E and p. L341V mutations had bulbar and limb onset, respectively. Moreover, a c.1166-14_1166-11delTACT mutation in the intron 7 was found in a living male patient with limb onset at age of 62. None of the patients carrying SQSTM1 mutation showed clinical evidence of concomitant Paget disease of bone or mutation of the valosin-containing protein gene. The mutation frequency of SQSTM1 was 0.98% in Chinese patients with SALS, which was lower than those in other racial populations.
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PMID:SQSTM1 mutations in Han Chinese populations with sporadic amyotrophic lateral sclerosis. 2413 88

Cdc48 (also called VCP and p97) is an abundant protein that plays essential regulatory functions in a broad array of cellular processes. Working with various cofactors, Cdc48 utilizes its ATPase activity to promote the assembly and disassembly of protein complexes. Here, we review key biological functions and regulation of Cdc48 in ubiquitin-related events. Given the broad employment of Cdc48 in cell biology and its intimate ties to human diseases (e.g., amyotrophic lateral sclerosis), studies of Cdc48 will bring significant insights into the mechanism and function of ubiquitin in health and diseases.
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PMID:Cdc48: a swiss army knife of cell biology. 2416 26


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