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)

TDP-43, a nuclear factor that functions in regulating transcription and alternative splicing, was recently identified as a component of the ubiquitin-positive, tau-negative inclusions specific for frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). In the present study, we carried out immunohistochemical and biochemical analyses of brains of Guamanians with the parkinsonism-dementia complex (G-PDC) using anti-TDP-43, anti-tau and anti-ubiquitin antibodies. Immunohistochemistry with anti-TDP-43 antibodies revealed various types of positive structures in the frontotemporal and hippocampal regions of G-PDC cases. Most of these structures were negative for tau. By immunoblot analysis with the TDP-43 antibody, an abnormal 45 kDa band, as well as a diffuse staining throughout the gel, was detected in the sarkosyl-insoluble fractions of G-PDC brains. Dephosphorylation has shown that abnormal phosphorylation takes place in the accumulated TDP-43 seen in FTLD-U and ALS. These results suggest that accumulation of TDP-43 is a common process in certain neurodegenerative disorders, including FTLD-U, ALS and G-PDC.
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PMID:TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. 1743 83

The rapid confirmation of the initial report by Neumann et al. (Science 314:130-133, 2006) that transactive response (TAR)-DNA-binding protein 43 (TDP-43) is the major disease protein linking frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) with and without motor neuron disease (MND) as well as amyotrophic lateral sclerosis (ALS) implies that TDP-43 proteinopathy underlies major forms of sporadic as well as familial FTLD and ALS. Not only was the identity of the ubiquitinated proteins that accumulate in neurons and glia of these disorders finally resolved, but it also was shown that pathologic TDP-43 was hyperphosphorylated, ubiquitinated and cleaved to generate C-terminal fragments in affected brain and spinal cord of FTLD-U and ALS. This review summarizes the growing evidence that TDP-43 proteinopathy is the common pathologic substrate linking FTLD and ALS, and it considers the implications of these findings for developing better strategies to diagnose and treat these neurodegenerative disorders.
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PMID:TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease. 1749 94

In a subset of patients, ALS is associated with frontotemporal dysfunction (ALS-FTD). Clinically, ALS-FTD may present with a variable spectrum of cognitive and behavioural deficits. We report a 53-year-old ALS-FTD patient developing inappropriate sexual behaviour (ISB) manifesting as a vigorous sexual drive with exhausting demands for sexual intercourse and physical aggressions against his wife. This distressing symptom could be alleviated with the selective serotonin reuptake inhibitor sertraline. ISB is an embarrassing symptom for most patients and their caregivers and may therefore be under-reported. Since effective treatment is available, we suggest an open and proactive discussion of sexual issues in this patient group.
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PMID:Inappropriate sexual behaviour in a case of ALS and FTD: successful treatment with sertraline. 1753 83

Pathological TDP-43 is the major disease protein in frontotemporal lobar degeneration characterized by ubiquitin inclusions (FTLD-U) with/without motor neuron disease (MND) and in amyotrophic lateral sclerosis (ALS). As Guamanian parkinsonism-dementia complex (PDC) or Guamanian ALS (G-PDC or G-ALS) of the Chamorro population may present clinically similar to FTLD-U and ALS, TDP-43 pathology may be present in the G-PDC and G-ALS. Thus, we examined cortical or spinal cord samples from 54 Guamanian subjects for evidence of TDP-43 pathology. In addition to cortical neurofibrillary and glial tau pathology, G-PDC was associated with cortical TDP-43 positive dystrophic neurites and neuronal and glial inclusions in gray and/or white matter. Biochemical analyses showed the presence of FTLD-U-like insoluble TDP-43 in G-PDC, but not in Guam controls (G-C). Spinal cord pathology of G-PDC or G-ALS was characterized by tau positive tangles as well as TDP-43 positive inclusions in lower motor neurons and glial cells. G-C had variable tau and negligible TDP-43 pathology. These results indicate that G-PDC and G-ALS are associated with pathological TDP-43 similar to FTLD-U with/without MND as well as ALS, and that neocortical or hippocampal TDP-43 pathology distinguishes controls from disease subjects better than tau pathology. Finally, we conclude that the spectrum of TDP-43 proteinopathies should be expanded to include neurodegenerative cognitive and motor diseases, affecting the Chamorro population of Guam.
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PMID:Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. 1803 49

TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate approximately 35 and approximately 25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.
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PMID:Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. 1789 24

The clinical entity of Amyotrophic Lateral Sclerosis with Frontotemporal Dementia (ALS-FTD) has only recently been recognized as an important neurodegenerative disease. As in isolated FTD, the behavioral and personality changes in ALS-FTD might be more characteristic than its cognitive changes. We aimed to characterize the behavioral and cognitive deficits in ALS-FTD, and contrast this profile with that of the most common form of dementia, AD, to assist ALS clinicians in recognizing the syndrome early in its course. Specifically, we hypothesized that a modified version of the Frontal Behavioral Inventory (FBI-mod), a brief questionnaire self-administered by a caregiver, along with just a few cognitive tests, would be clinically useful in distinguishing the dementia in ALS-FTD from the dementia of AD. We administered a battery of neuropsychological tests to 15 patients who met established criteria for Amyotrophic Lateral Sclerosis with Frontotemporal Dementia and to 30 patients who met established criteria for probable Alzheimer's disease. The FBI-mod was completed by caregivers. We found that the FBI-mod, age-corrected Z scores for the Mini-Mental State Examination (MMSE), a test of delayed recall, and a word fluency measure together discriminated between ALS-FTD and AD. ALS-FTD was characterized by more abnormal FBI scores and poor word fluency, in the presence of relatively normal overall cognitive status (MMSE) and/or delayed recall.
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PMID:Distinctions between the dementia in amyotrophic lateral sclerosis with frontotemporal dementia and the dementia of Alzheimer's disease. 1791 49

TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or alpha-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with alpha-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.
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PMID:Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies. 1796 32

TAR DNA-binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein that functions in regulating transcription and alternative splicing, was identified as a component of ubiquitin-positive tau-negative cytoplasimic inclusions in frontotemporal lobar degeneration (FTLD-U), and subsequently of ubiquitin-positive skein-like inclusions in amyotrophic lateral sclerosis (ALS). Dephosphorylation treatment of sarkosyl-insoluble fractions have suggested that abnormal phosphorylation takes place in the deposited TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43. This article reviews the ubiquitin-positive inclusions in ALS and the recent discovery of TDP-43 in tau-negative inclusions in FTLD-U and ALS. We also discuss the biological implications of these findings for the pathogenesis of ALS.
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PMID:[Component of ubiquitin-positive inclusions in ALS]. 1796 58

Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD-MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD-MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD-MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD-MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining ("pre-inclusion") was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD-MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.
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PMID:Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. 1803 49

There is increasing recognition of a clinical overlap between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent advances in our understanding of the neuropathologic, biochemical, and genetic basis of these conditions provides evidence for a common underlying pathogenesis. The neuropathology in most cases of FTD with ALS is a subtype of frontotemporal lobar degeneration, characterized by neuronal inclusions that are immunoreactive for ubiquitin but not tau (frontotemporal lobar degeneration with ubiquitinated inclusions). These cases show significant pathologic overlap with clinically pure FTD and those with classic ALS. Moreover, the ubiquitinated pathologic protein in all these conditions has recently been identified as TDP-43. A number of families have been reported with autosomal dominant FTD-ALS linked to chromosome 9p and these also have TDP-43-positive frontotemporal lobar degeneration with ubiquitinated inclusions pathology. Together, these findings suggest that FTD-ALS is part of a clinicopathologic spectrum of disease, now identified as TDP-43 proteinopathies.
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PMID:The neuropathology of FTD associated With ALS. 1809 Apr 23


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