UMLS:C0002736 - FACTA Search

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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation of hyperphosphorylated, ubiquitinated and N-terminally truncated TAR DNA-binding protein (TDP-43) is the pathological hallmark lesion in most familial and sporadic forms of FTLD-U and ALS, which can be subsumed as TDP-43 proteinopathies. In order to get more insight into the role of abnormal phosphorylation in the disease process, the identification of specific phosphorylation sites and the generation of phosphorylation-specific antibodies are mandatory. Here, we developed and characterized novel rat monoclonal antibodies (1D3 and 7A9) raised against phosphorylated S409/410 of TDP-43. These antibodies were used to study the presence of S409/410 phosphorylation by immunohistochemistry and biochemical analysis in a large series of 64 FTLD-U cases with or without motor neuron disease including familial cases with mutations in progranulin (n = 5), valosin-containing protein (n = 4) and linkage to chromosome 9p (n = 4), 18 ALS cases as well as other neurodegenerative diseases with concomitant TDP-43 pathology (n = 5). Our data demonstrate that phosphorylation of S409/410 of TDP-43 is a highly consistent feature in pathologic inclusions in the whole spectrum of sporadic and familial forms of TDP-43 proteinopathies. Physiological nuclear TDP-43 was not detectable with these mAbs by immunohistochemistry and by immunoblot analyses. While the accumulation of phosphorylated C-terminal fragments was a robust finding in the cortical brain regions of FTLD-U and ALS, usually being much more abundant than the phosphorylated full-length TDP-43 band, spinal cord samples revealed a predominance of full-length TDP-43 over C-terminal fragments. This argues for a distinct TDP-43 species composition in inclusions in cortical versus spinal cord cells. Overall, these mAbs are powerful tools for the highly specific detection of disease-associated abnormal TDP-43 species and will be extremely useful for the neuropathological routine diagnostics of TDP-43 proteinopathies and for the investigation of emerging cellular and animal models for TDP-43 proteinopathies.
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PMID:Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. 1912 55

The disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) was identified recently as the TDP-43 (TAR DNA-binding protein 43), thereby providing a molecular link between these two disorders. In FTLD-U and ALS, TDP-43 is redistributed from its normal nuclear localization to form cytoplasmic insoluble aggregates. Moreover, pathological TDP-43 is abnormally ubiquitinated, hyperphosphorylated, and N-terminally cleaved to generate C-terminal fragments (CTFs). However, the specific cleavage site(s) and the biochemical properties as well as the functional consequences of pathological TDP-43 CTFs remained unknown. Here we have identified the specific cleavage site, Arg(208), of a pathological TDP-43 CTF purified from FTLD-U brains and show that the expression of this and other TDP-43 CTFs in cultured cells recapitulates key features of TDP-43 proteinopathy. These include the formation of cytoplasmic aggregates that are ubiquitinated and abnormally phosphorylated at sites found in FTLD-U and ALS brain and spinal cord samples. Furthermore, we observed splicing abnormalities in a cell culture system expressing TDP-43 CTFs, and this is significant because the regulation of exon splicing is a known function of TDP-43. Thus, our results show that TDP-43 CTF expression recapitulates key biochemical features of pathological TDP-43 and support the hypothesis that the generation of TDP-43 CTFs is an important step in the pathogenesis of FTLD-U and ALS.
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PMID:Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies. 1916 85

It has been reported that widespread multisystem degeneration can occur in patients with sporadic amyotrophic lateral sclerosis (SALS) who have survived for long periods with artificial respiratory support (ARS). We report a case of SALS of 8 years and 8 months duration in a 71-year-old woman, who received ARS for 7 years and 8 months. In this patient, the symptoms at the early stage were those of typical ALS, and a totally locked-in state with frontal lobe atrophy appeared a few years after the start of ARS. At autopsy, marked atrophy of the frontal lobe and brainstem tegmentum was evident. Microscopically, widespread multisystem degeneration with obvious neuronal loss was a feature. Bunina bodies and ubiquitinated inclusions were observed in the remaining lower motor neurons. Of interest was that Lewy body-like hyaline inclusions (LBHIs), which were later shown to be immunnoreactive (ir) for 43-kDa TAR DNA-binding protein (TDP-43) and ubiquitin, were also detected in neurons in various regions of the nervous system, including the lower and upper motor neuron nuclei. The distributions of neurons with TDP-43-ir and ubiquitin-ir cytoplasmic inclusions were also widespread in the nervous system, and in each region, the numbers of these neurons were apparently larger than those of neurons with LBHIs. Importantly, double-labeling immunofluorescence revealed that the widespread TDP-43-ir inclusions were often ubiqutinated. In conclusion, the entire pathological picture appeared to correspond well to the patient's long-standing, progressive disease, including the TDP-43 pathology with ubiquitination. These findings further strengthen the idea that TDP-43 abnormality is closely associated with the pathogenesis of SALS.
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PMID:Sporadic amyotrophic lateral sclerosis: Widespread multisystem degeneration with TDP-43 pathology in a patient after long-term survival on a respirator. 1917 Aug 93

TDP-43 is a pathogenic protein: its normal function in binding to UG-rich RNA is related to cystic fibrosis, and inclusion of its C-terminal fragments in brain cells is directly linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here we report the 1.65 A crystal structure of the C-terminal RRM2 domain of TDP-43 in complex with a single-stranded DNA. We show that TDP-43 is a dimeric protein with two RRM domains, both involved in DNA and RNA binding. The crystal structure reveals the basis of TDP-43's TG/UG preference in nucleic acids binding. It also reveals that RRM2 domain has an atypical RRM-fold with an additional beta-strand involved in making protein-protein interactions. This self association of RRM2 domains produced thermal-stable RRM2 assemblies with a melting point greater than 85 degrees C as monitored by circular dichroism at physiological conditions. These studies thus characterize the recognition between TDP-43 and nucleic acids and the mode of RRM2 self association, and provide molecular models for understanding the role of TDP-43 in cystic fibrosis and the neurodegenerative diseases related to TDP-43 proteinopathy.
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PMID:Structural insights into TDP-43 in nucleic-acid binding and domain interactions. 1917 64

Frontotemporal degeneration (FTD), formerly known as Pick's disease has become recognized as a distinct and relatively common entity encompassing behavioural (bvFTD language (PPA) and extrapyramidal (CBD/PSP) presentations. Further clinical subdivisions such as semantic dementia(SD), and pathological subtypes such as mesial temporal sclerosis increase the complexity of diagnosis.The relatively younger age of onset, the typical presentations of syndromes and focal asymmetrical frontotemporal atrophy on imaging allows experienced clinicians to make the diagnosis confidently as long as the overlap between the syndromes is recognized. There is also an overlap with ALS pathologically and clinically. The underlying histology in FTD/Pick complex is ubiquitin positive tau and synuclein negative neuronal inclusions (FTLD-U) in more than half of autopsies and tau positive CBD/PSP/ Pick bodies (FTLD-T) in the rest. The clinical syndromes of bvFTD and SD are likely associated with FTLD-U and PPA/CBDS/PSP with FTLD-T, but there is too much overlap to predict the pathology from the clinical syndromes reliably. The ubiquitin-tau pathological dichotomy is best considered under the Pick complex umbrella to allow for the significant overlap. So far trazodone in behavior and galantamine in aphasia had symptomatic benefit in small trials and SSRI-sand antipsychotics in uncontrolled reports were used as symptomatic therapies. Recent discoveries of tau and progranulin (in the ubiquitin-positive cases) mutations on chromosome 17 and other mutations on chromosome 3 and 9 in the high incidence of autosomal dominant families and a common protein abnormality, the TDP-43 in FTLD-U and ALS are likely to be important in finding therapeutic targets.
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PMID:Clinical features and diagnosis of frontotemporal dementia. 1918 72

The mechanisms involved in selective motor neuron degeneration in amyotrophic lateral sclerosis remain unknown more than 135 years after the disease was first described. Although most cases have no known cause, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been implicated in a fraction of familial cases of the disease. Transgenic mouse models with mutations in the SOD1 gene and other ALS genes develop pathology reminiscent of the disorder, including progressive death of motor neurons, and have provided insight into the pathogenesis of the disease but have consistently failed to predict therapeutic efficacy in humans. However, emerging research has demonstrated that mutations and pathology associated with the TDP-43 gene and protein may be more common than SOD1 mutations in familial and sporadic ALS. Putative mechanisms of toxicity targeting motor neurons include oxidative damage, accumulation of intracellular aggregates, mitochondrial dysfunction, defects in axonal transport, growth factor deficiency, aberrant RNA metabolism, glial cell pathology, and glutamate excitotoxicity. Convergence of these pathways is likely to mediate disease onset and progression.
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PMID:Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. 1919 4

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per 100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio approximately 1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs. Gradually, spasticity may develop in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solid or liquids, and limbs symptoms can develop almost simultaneously with bulbar symptoms, and in the vast majority of cases will occur within 1-2 years. Paralysis is progressive and leads to death due to respiratory failure within 2-3 years for bulbar onset cases and 3-5 years for limb onset ALS cases. Most ALS cases are sporadic but 5-10% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 2-5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations. The pathological hallmarks comprise loss of motor neurones with intraneuronal ubiquitin-immunoreactive inclusions in upper motor neurones and TDP-43 immunoreactive inclusions in degenerating lower motor neurones. Signs of upper motor neurone and lower motor neurone damage not explained by any other disease process are suggestive of ALS. The management of ALS is supportive, palliative, and multidisciplinary. Non-invasive ventilation prolongs survival and improves quality of life. Riluzole is the only drug that has been shown to extend survival.
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PMID:Amyotrophic lateral sclerosis. 1919 1

Tau-negative and ubiquitin-positive inclusions (UPI) are the pathological hallmarks of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, TDP-43, a heterogeneous nuclear ribonucleoprotein was identified as a component of these UPI. However, it remains to be determined whether TDP-43 is the major component of UPI, because only antibodies recognizing both normal and abnormal TDP-43 have been available. We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43. Of the generated antibodies, pS379, pS403/404, pS409, pS410 and pS409/410 clearly labeled UPI and glial cytoplasmic inclusions but not the nuclei. Immunoblot analyses of sarkosyl insoluble fractions demonstrated that the phosphorylation-specific antibodies recognized TDP-43 at -45 kDa, smearing substances and the -25 kDa fragment, all of which were present in the brains of FTLD-U and ALS but not controls. These antibodies did not recognize normal TDP-43 at 43 kDa. These results clearly indicate that abnormally phosphorylated full-length TDP-43 and the C-terminal fragments are the major component of UPI in FTLD-U and ALS. These findings together with recent discovery of mutations in the TDP-43 gene in ALS strongly suggest that TDP-43 is the
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PMID:[Significance of the TDP-43 deposition in FTLD-U and ALS]. 1919 42

Since the discovery of neuropathological lesions made of TDP-43 and ubiquitin proteins in cases of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), there is a burst of effort on finding related familial mutations and developing animal models. We used an adeno-associated virus (AAV) vector for human TDP-43 expression targeted to the substantia nigra (SN) of rats. Though TDP-43 was expressed mainly in neuronal nuclei as expected, it was also expressed in the cytoplasm, and dotted along the plasma membrane of neurons. Cytoplasmic staining was both diffuse and granular, indicative of preinclusion lesions, over 4 weeks. Ubiquitin deposited in the cytoplasm, specifically in the TDP-43 group, and staining for microglia was increased dose-dependently by 1-2 logs in the TDP-43 group, while neurons were selectively obliterated. Neuronal death induced by TDP-43 was pyknotic and apoptotic. TDP-43 gene transfer caused loss of dopaminergic neurons in the SN and their axons in the striatum. Behavioral motor dysfunction resulted after TDP-43 gene transfer that was vector dose-dependent and progressive over time. The cytoplasmic expression, ubiquitination, and neurodegeneration mimicked features of the TDP-43 diseases, and the gliosis, apoptosis, and motor impairment may also be relevant to TDP-43 disease forms involving nigrostriatal degeneration.
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PMID:Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig's disease in rats via TDP-43 overexpression. 1922 71

Recent studies identified rare missense mutations in amyotrophic lateral sclerosis (ALS) patients in the TARDBP gene encoding TAR DNA binding protein (TDP)-43, the major protein of the ubiquitinated inclusions (UBIs) found in affected motor neurons (MNs). The aim of this study was to further define the spectrum of TARDBP mutations in a large cohort of 666 Italian ALS patients (125 familial and 541 sporadic cases). The entire coding region was sequenced in 281 patients, while in the remaining 385 cases only exon 6 was sequenced. In 18 patients, of which six are familial, we identified 12 different heterozygous missense mutations (nine novel) all locating to exon 6, which were absent in 771 matched controls. The c.1144G>A (p.A382T) variation was observed in seven patients, thus representing the most frequent TARDBP mutation in ALS. Analysis of microsatellites surrounding the TARDBP gene indicated that p.A382T was inherited from a common ancestor in 5 of the 7 patients. Altogether, the frequency of TARDBP gene mutations appears to be particularly high in Italian ALS patients compared to individuals of mainly Northern European origin (2.7% vs. 1%). Western blot analysis of lymphocyte extracts from two patients carrying the p.A382T and p.S393L TARDBP mutations showed the presence of lower molecular weight TDP-43 bands, which were more abundant than observed in healthy controls and patients negative for TARDBP mutations. In conclusion, this report contributes to the demonstration of the causative role of the TARDBP gene in ALS pathogenesis and indicates that mutations may affect the stability of the protein even in nonneuronal tissues.
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PMID:High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. 1922 87

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