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)

For the vast majority of cases of amyotrophic lateral sclerosis (ALS) the etiology remains unknown. After the discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial ALS, several transgenic mouse lines have been generated with various forms of SOD1 mutants overexpressed at different levels. Studies with these mice yielded complex results with multiple targets of damage in disease including mitochondria, proteasomes, and secretory pathways. Many unexpected discoveries were made. For instance, the toxicity of mutant SOD1 seems unrelated to copper-mediated catalysis but rather to formation of misfolded SOD1 species and aggregates. Transgenic studies revealed a potential role of wtSOD1 in exacerbating mutant SOD1-mediated disease. Another key finding came from chimeric mouse studies and from Cre-lox mediated gene deletion experiments which have highlighted the importance of non-neuronal cells in the disease progression. Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport. Recently, the generation of new animal models of ALS has been made possible with the discovery of ALS-linked mutations in other genes encoding for alsin, dynactin, senataxin, VAPB, TDP-43 and FUS. Following the discovery of mutations in the TARDBP gene linked to ALS, there have been some reports of transgenic mice with high level overexpression of WT or mutant forms of TDP-43 under strong gene promoters. However, these TDP-43 transgenic mice do not exhibit all pathological features the human ALS disease. Here, we will describe these new TDP-43 transgenic mice and discuss their validity as animal models of human ALS.
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PMID:ALS pathogenesis: recent insights from genetics and mouse models. 2072 92

TAR DNA-binding protein-43 (TDP-43), a DNA/RNA-binding protein involved in RNA transcription and splicing, has been associated with the pathophysiology of neurodegenerative diseases, including ALS. However, the function of TDP-43 in motor neurons remains undefined. Here we use both gain- and loss-of-function approaches to determine roles of TDP-43 in motor neurons. Mice expressing human TDP-43 in neurons exhibited growth retardation and premature death that are characterized by abnormal intranuclear inclusions composed of TDP-43 and fused in sarcoma/translocated in liposarcoma (FUS/TLS), and massive accumulation of mitochondria in TDP-43-negative cytoplasmic inclusions in motor neurons, lack of mitochondria in motor axon terminals, and immature neuromuscular junctions. Whereas an elevated level of TDP-43 disrupts the normal nuclear distribution of survival motor neuron (SMN)-associated Gemini of coiled bodies (GEMs) in motor neurons, its absence prevents the formation of GEMs in the nuclei of these cells. Moreover, transcriptome-wide deep sequencing analysis revealed that a decrease in abundance of neurofilament transcripts contributed to the reduction of caliber of motor axons in TDP-43 mice. In concert, our findings indicate that TDP-43 participates in pathways critical for motor neuron physiology, including those that regulate the normal distributions of SMN-associated GEMs in the nucleus and mitochondria in the cytoplasm.
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PMID:Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. 2073 50

Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.
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PMID:TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. 2086 52

Amyotrophic lateral sclerosis (ALS) is an incurable disease resulting from the deterioration of motor neurons. The onset of disease typically occurs in the fifth decade of life and progresses rapidly; death occurs for 75% of patients within 5 years. The only drug that is available to treat ALS is riluzole, which extends survival by just 2-3 months. Thus, new therapeutic directions are being sought to prolong the lifespan of ALS patients. Since the discovery of SOD1 as a genetic determinant of ALS in 1993, SOD1-models of ALS have been extensively employed for the development of ALS therapeutics. Novel genetic targets are now under investigation following the recent discoveries linking TDP-43, FUS/TLS, angiogenin, KIFAP3 and UNC13A to ALS. In this review, we present several of the genetic contributors to both sporadic and familial forms of ALS and discuss their potential as therapeutic targets for this devastating disease.
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PMID:Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets. 2094 85

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons that causes progressive weakness and death. The breadth of research in ALS continues to grow with exciting new discoveries in disease pathogenesis and potential future therapeutics. There is a growing list of identified mutations in familial ALS, including those in genes encoding TDP-43 and FUS/TLS, which are expanding our understanding of the role of RNA modulation in ALS pathogenesis. There is a greater appreciation for the role of glial cells in motor neuron disease. Mitochondrial dysfunction is also being shown to be critical for motor neuron degeneration. In addition to pharmacotherapy, there are promising early developments with therapeutic implications in the areas of RNA interference, stem cell therapies, viral vector-mediated gene therapy, and immunotherapy. With greater understanding of ALS pathogenesis and exciting new therapeutic technologies, there is hope for future progress in treating this disease.
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PMID:Research advances in amyotrophic lateral sclerosis, 2009 to 2010. 2108 Feb 40

TLS (translocated in liposarcoma), also known as FUS (fused in sarcoma), is an RNA/DNA-binding protein that plays regulatory roles in transcription, pre-mRNA splicing and mRNA transport. Mutations in TLS are responsible for familial amyotrophic lateral sclerosis (ALS) type 6. Furthermore, TLS-containing intracellular inclusions are found in polyglutamine diseases, sporadic ALS, non-SOD1 familial ALS and a subset of frontotemporal lobar degeneration, indicating a pathological significance of TLS in a wide variety of neurodegenerative diseases. Here, we identified TLS domains that determine intracellular localization of the murine TLS. Among them, PY-NLS located in the C-terminus is a strong determinant of intracellular localization as well as splicing regulation of an E1A-derived minigene. Disruption of PY-NLS promoted the formation of cytoplasmic granules that were partially overlapped with stress granules and P-bodies. Some of the ALS-linked mutations altered both intracellular localization and splicing regulation of TLS, while most mutations alone did not affect splicing regulation. However, phospho-mimetic substitution of Ser505 (or Ser513 in human) could enhance the effects of ALS mutations, highlighting interplay between post-translational modification and ALS-linked mutations. These results demonstrate that ALS-linked mutations can variably cause loss of nuclear functions of TLS depending on the degree of impairment in nuclear localization.
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PMID:Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. 2110 27

We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.
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PMID:Phenotypic heterogeneity in a SOD1 G93D Italian ALS family: an example of human model to study a complex disease. 2112 Jun 36

Our objective was to investigate the prevalence of FUS/TLS mutations in a Catalan familial ALS cohort undergoing a mutational study for SOD1 in 2006. We screened 25 probands from non-SOD1 families for FUS/TLS mutations. We identified two FALS probands with FUS/TLS mutations. One carried a C-to-T transition at nucleotide position 1561 (c.1561C>T) producing a p.R521C sequence change at protein level. The phenotype was characterized by a young age at onset (38.2 years old), proximal limb girdle weakness, predominant lower motor neuron signs and dropped head. Survival time ranged from 10 to 36 months. Obligate asymptomatic carriers were detected. Our second ALS6 pedigree carried a C-to-T transition at nucleotide position 1528 (c.1528G>A) producing a p.K510E sequence change at protein level. The phenotype was of an early onset (<40 years old), predominant lower motor neuron disease with short survival (nine months). In conclusion, these are the first two FUS/TLS mutations identified in Spain. The prevalence of this form of FALS (8%) is similar to the Dutch and British populations. FUS/TLS mutations are the second most common cause of FALS in our population.
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PMID:FUS/TLS gene mutations are the second most frequent cause of familial ALS in the Spanish population. 2112 70

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are clinically overlapping neurodegenerative disorders whose pathophysiology remains incompletely understood. ALS initiates in a discrete location, and typically progresses in a pattern consistent with spread of the degenerative process to involve neighboring regions of the motor system, although the basis of the apparent "spread" remains elusive. Recently mutations in two RNA binding proteins, TDP-43 and FUS, were identified in patients with familial ALS. In addition to being involved in numerous events related to RNA metabolism, each forms aggregates in neurons in ALS and FTLD. Recent evidence also indicates that both TDP-43 and FUS contain prion-related domains rich in glutamine (Q) and asparagine (N) residues, and in the case of TDP-43 this is the location of most disease causing mutations. This review discusses the potential relevance of the prion-related domains in TDP-43 and FUS in normal physiology, pathologic aggregation, and disease progression in ALS and FTLD.
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PMID:Implications of the prion-related Q/N domains in TDP-43 and FUS. 2113 80

Rapid advances were made in the knowledge of amyotrophic lateral sclerosis (ALS) with the recent identification of TARDBP and FUS mutations in familial ALS. More recently, FUS-positive inclusions were found in a subset of TDP-43-negative frontotemporal lobar degeneration (FTLD) prompting us to analyze FUS in FTLD and FTLD-ALS patients. The p.Arg521His mutation was identified in a patient who initially had behavioral disorders and rapidly developed ALS. Although the frequency of mutations is low, our study enlarges the phenotypes associated with FUS mutations and shows that FUS could also play a direct pathogenic role in FTLD spectrum of diseases.
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PMID:FUS mutations in frontotemporal lobar degeneration with amyotrophic lateral sclerosis. 2115 17


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