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 (43-kDa TAR DNA-binding protein) is a major constituent of ubiquitin-positive cytosolic aggregates present in neurons of patients with amyotrophic lateral sclerosis (ALS) and ubiquitin-positive fronto-temporal lobar degeneration (FTLD-U). Inherited mutations in TDP-43 have been linked to familial forms of ALS, indicating a key role for TDP-43 in disease pathogenesis. Here, we describe a Drosophila melanogaster model of TDP-43 proteinopathy. Expression of wild-type human TDP-43 protein in Drosophila motor neurons led to motor dysfunction and dramatic reduction of life span. Interestingly, coexpression of ubiquilin 1, a previously identified TDP-43-interacting protein with suspected functions in autophagy and proteasome targeting, reduced steady-state TDP-43 expression but enhanced the severity of TDP-43 phenotypes. Finally, ectopically expressed TDP-43 was largely localized to motor neuron nuclei, suggesting that expression of wild-type TDP-43 alone is detrimental even in the absence of cytosolic aggregation. Our findings demonstrate that TDP-43 exerts cell-autonomous neurotoxicity in Drosophila and further imply that dose-dependent alterations of TDP-43 nuclear function may underlie motor neuron death in ALS.
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PMID:Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). 2015 90

The clinical features of a Japanese family with autosomal dominant adult-onset amyotrophic lateral sclerosis (ALS) are reported. Weakness initially affected the bulbar musculature, with later involvement of the extremities. Genetic studies failed to detect any mutations of the Cu/Zn superoxide dismutase-1 (SOD1) and Dynactin1 (DCTN1) genes, but revealed a single base pair change from wild-type adenine to guanine at position 1009 in TAR-DNA-binding protein (TDP-43), resulting in a methionine-to-valine substitution at position 337. The immunohistochemical study on autopsied brain of the proband's aunt showed TDP-43-positive cytoplasmic inclusions in the anterior horn cells of the spinal cord and in the hypoglossal nucleus, as well as glial cytoplasmic inclusions in the precentral gyrus, suggesting that a neuroglial proteinopathy was related to TDP-43. In conclusion, a characteristic clinical phenotype of familial ALS with initial bulbar symptoms occurred in this family with TDP-43 M337V substitution, the pathomechanism of which should be elucidated.
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PMID:TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan. 2015 40

There is an overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Some 5-10% of ALS patients show changes in their behaviour and personality that are characteristic of FTD and about 10% of FTD patients develop ALS. Mild cognitive impairment occurs in 30% of ALS patients. The progressive decline of muscle strength in ALS patients and social skills in FTD patients places severe demands on the patient and his or her contacts. In some ALS and FTD patients, ubiquitin-positive inclusions have been found in the hippocampus and anterior horn cells. In patients with familial FTD who have ubiquitin-positive inclusions, mutations have been found in the progranulin (PGRN) gene. TAR-DNA-binding protein-43, encoded by the TARDBP gene, has recently been identified as a constituent of the ubiquitin inclusions. TARDBP and PGRN mutations are found in patients with ALS. The overlapping characteristics provide clues for further research into the pathogenesis of ALS and FTD.
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PMID:[Amyotrophic lateral sclerosis and frontotemporal dementia: overlapping characteristics]. 2017 58

Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.
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PMID:Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. 2018 46

Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions, and the discovery that mutations in the TDP-43 gene cause ALS, much effort has been directed towards establishing how TDP-43 contributes to the development of neurodegeneration. Although few in vivo models are presently available, findings thus far strongly support the involvement of abnormally modified TDP-43 in promoting TDP-43 aggregation and cellular mislocalization. Therefore, TDP-43-mediated neurotoxicity is likely to result from a combination of toxic gains of function conferred by TDP-43 inclusions as well as from the loss of normal TDP-43 function. Nonetheless, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neuronal death. Moreover, little is currently known about the roles of TDP-43, both in the nucleus and the cytoplasm, making it difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. This review will summarize what is currently understood regarding normal TDP-43 function and the involvement of TDP-43 in neurodegeneration, and will also highlight some of the many remaining questions in need of further investigation.
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PMID:Review: transactive response DNA-binding protein 43 (TDP-43): mechanisms of neurodegeneration. 2020 22

Both the appearance of cytoplasmic inclusions containing phosphorylated TAR DNA-binding protein (TDP-43) and inefficient RNA editing at the GluR2 Q/R site are molecular abnormalities observed specifically in motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS). The purpose of this study is to determine whether a link exists between these two specific molecular changes in ALS spinal motor neurons. We immunohistochemically examined the expression of adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes GluR2 Q/R site-editing, and the expression of phosphorylated and non-phosphorylated TDP-43 in the spinal motor neurons of patients with sporadic ALS. We found that all motor neurons were ADAR2-positive in the control cases, whereas more than half of them were ADAR2-negative in the ALS cases. All ADAR2-negative neurons had cytoplasmic inclusions that were immunoreactive to phosphorylated TDP-43, but lacked non-phosphorylated TDP-43 in the nucleus. Our results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology.
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PMID:TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. 2037 15

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases with clinical and pathological overlap. Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and FTLD, combined with the abnormal aggregation of these proteins, have initiated a shifting paradigm for the underlying pathogenesis of multiple neurodegenerative diseases. TDP-43 and FUS/TLS are both RNA/DNA-binding proteins with striking structural and functional similarities. Their association with ALS and other neurodegenerative diseases is redirecting research efforts toward understanding the role of RNA processing regulation in neurodegeneration.
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PMID:TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. 2040 Apr 60

Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.
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PMID:Mutations of optineurin in amyotrophic lateral sclerosis. 2042 14

Trans-activation response DNA-binding protein (TDP-43) accumulation is the major component of ubiquitinated protein inclusions found in patients with amyotrophic lateral sclerosis, and frontotemporal lobar degeneration with TDP-43 positive ubiquitinated inclusions, recently relabelled the 'TDP-43 proteinopathies'. TDP-43 is predominantly located in the nucleus, however, in disease it mislocalizes to the cytoplasm where it aggregates to form hallmark pathological inclusions. The identification of TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis cases confirms its pathogenic role; but it is wild-type TDP-43 that is deposited in the vast majority of TDP-43 proteinopathies, implicating other unknown factors for its mislocalization and aggregation. One such mechanism may be defective nuclear import of TDP-43 protein, as a disruption of its nuclear localization signal leads to mislocalization and aggregation of TDP-43 in the cytoplasm. In order to explore the factors that regulate the nuclear import of TDP-43, we used a small interfering RNA library to silence 82 proteins involved in nuclear transport and found that knockdowns of karyopherin-beta1 and cellular apoptosis susceptibility protein resulted in marked cytoplasmic accumulation of TDP-43. In glutathione S-transferase pull-down assays, TDP-43 bound to karyopherin-alphas, thereby confirming the classical nuclear import pathway for the import of TDP-43. Analysis of the expression of chosen nuclear import factors in post-mortem brain samples from patients with TDP-43 positive frontotemporal lobar degeneration, and spinal cord samples from patients with amyotrophic lateral sclerosis, revealed a considerable reduction in expression of cellular apoptosis susceptibility protein in frontotemporal lobar degeneration. We propose that cellular apoptosis susceptibility protein associated defective nuclear transport may play a mechanistic role in the pathogenesis of the TDP-43 positive frontotemporal lobar degeneration.
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PMID:Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration. 2047 55

Frontotemporal lobar degeneration (FTLD) is a clinical syndrome characterized by behavioral and language difficulties, which refers to a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative disorders. Familial FTLD has been linked to mutations in several genes: the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP) and charged multivescicular body protein 2B (CHMP2B), and genetic locus on chromosome 9p linked to familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The associated neuropathology is characterized by selective degeneration of the frontal and temporal lobes with the neuronal and/or glial inclusions. The current classification of FTLD neuropathology is based on the major constituent protein of them: tau, TAR DNA-binding protein of 43 kD (TDP-43), and fused in sarcoma (FUS). Abnormal phosphorylation, ubiquitination, and proteolytic cleavage are the common pathologic signature of tau and TDP-43 accumulated in diseased brains. Recent findings of TDP-43 and FUS reveal that FTLD and ALS share a common mechanism of pathogenesis. This review focuses on the current understanding of the molecular neuropathology of FTLD, and their relevance to the development of the therapeutics.
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PMID:[The molecular pathology of frontotemporal lobar degeneration]. 2049 55


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