Is TDP-43 inclusion a common feature in all ALS patients?
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TDP-43 inclusion is a common feature in most cases of amyotrophic lateral sclerosis (ALS) . TDP-43 is a DNA/RNA binding protein that is involved in RNA metabolism and dysfunctions in TDP-43, along with cytoplasmic aggregation, are central to the pathogenicity of ALS . TDP-43-positive neuronal cytoplasmic inclusions are identified in the brain and spinal cord of ALS patients . These inclusions can take various forms, including skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining . Additionally, loss of TDP-43 function leads to the inclusion of cryptic exons in transcripts, which can generate de novo proteins . Therefore, TDP-43 inclusion is a common feature in ALS, and understanding the biology and pathology of TDP-43 may provide insights into novel therapeutic strategies for the disease .
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| Papers (5) | Insight |
|---|---|
| The paper does not explicitly state whether TDP-43 inclusion is a common feature in all ALS patients. | |
| The paper states that TDP-43 pathology, including ubiquitinated and phosphorylated inclusions, is commonly linked to neurodegeneration in ALS and FTLD-TDP. Therefore, TDP-43 inclusion is a common feature in most cases of ALS. | |
| The answer to the query is not provided in the paper. The paper discusses the generation of de novo proteins from mis-spliced mRNA transcripts in TDP-43-related ALS/FTD, but it does not mention whether TDP-43 inclusion is a common feature in all ALS patients. | |
| The paper states that TDP-43 inclusion is the hallmark pathology in >95% of ALS patients, indicating that it is a common feature in most ALS cases. | |
| The paper does not directly answer the question about whether TDP-43 inclusion is a common feature in all ALS patients. The paper focuses on the loss of TDP-43 splicing repression in ALS, particularly in C9ORF72-associated ALS. |
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Amygdala subfield in TDP-434 answersTDP-43 pathology in the amygdala has been observed in various neurodegenerative diseases, including limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 inclusions have been found in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), including amyotrophic lateral sclerosis. TDP-43 burden in the hippocampus has been associated with inward deformation of the hippocampal surface, suggesting a unique effect of TDP-43 on hippocampal structure. In multiple system atrophy (MSA), TDP-43 pathology is rare and mainly localized to the medial temporal lobe, including the amygdala. Hippocampal shape deformity in zones approximating CA1 has been identified as a potential biomarker for postmortem AD pathology, but no significant association has been found between TDP-43 pathology and hippocampal shape deformity.
What is the role of TDP-43 in cryptic exons?5 answersTDP-43 plays a crucial role in repressing the inclusion of cryptic exons during RNA splicing. Loss of TDP-43 function leads to the inclusion of these cryptic exons in various transcripts, resulting in aberrant splicing patterns. TDP-43 directly binds to the RNA of specific genes, such as UNC13A and Neurofascin, and represses the inclusion of cryptic exons in their transcripts. The presence of TDP-43 is necessary for the proper assembly and maintenance of paranodes in Schwann cells, which are essential for rapid nerve conduction. Additionally, other RNA-binding proteins, such as hnRNP L, hnRNP A1, and hnRNP A2B1, also contribute to the regulation of cryptic exon inclusion, independently of TDP-43. Overall, TDP-43 is a key player in preventing the inclusion of cryptic exons during RNA splicing, and its dysfunction can lead to pathological consequences in neurodegenerative diseases like ALS and FTD.
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What are the pathological features or hallmarks of Limbic predominant age-related TDP-43 encephalopathy (LATE).?5 answersLimbic predominant age-related TDP-43 encephalopathy (LATE) is characterized by the presence of transactive response DNA-binding protein 43 kDa (TDP-43) proteinopathy. LATE is often comorbid with Alzheimer's disease neuropathologic change (ADNC) and is associated with more severe ADNC, hippocampal sclerosis, and brain arteriolosclerosis copathologies. LATE-NC is commonly found in the elderly population and is associated with cognitive impairment. It is characterized by stages 2 or 3 of TDP-43 proteinopathy. LATE-NC can be differentiated from AD based on clinical and cognitive features. Individuals with LATE pathology tend to live longer, have a later onset of cognitive decline, and are more likely to be diagnosed as cognitively normal at baseline compared to those with AD pathology. The presence of LATE-NC is associated with a different pattern of behavioral and cognitive performance, particularly in individuals with low/intermediate ADNC burden. The MRI signature of LATE-NC has not been fully determined, but abnormalities in white matter structural integrity may be detected using diffusion tensor imaging.
What is the role of TDP-43 cryptic exons in Alzheimer's disease and other neurodegenerative disorders?5 answersTDP-43 cryptic exons play a role in Alzheimer's disease and other neurodegenerative disorders by contributing to the pathology and progression of these diseases. TDP-43 is a protein that forms aggregates in the central nervous system and is associated with diseases such as ALS, FTD, AD, and LATE ^[Sekar et al.]. The accumulation of TDP-43 aggregates is linked to smaller hippocampal volumes, more severe cognitive impairment, and a clinically more severe degree of dementia in AD patients ^[Tomé et al.]. Additionally, TDP-43 aggregates can be transferred from cell-to-cell in a prion-like manner, contributing to the spread of pathology in neurodegenerative diseases ^[Jo et al.]. The crosstalk between TDP-43 and other proteins, such as tau and amyloid-β, has been observed in AD brains, suggesting an interaction between these proteins during AD pathogenesis ^[Tomé et al.]. Overall, TDP-43 cryptic exons are involved in the pathogenesis and progression of neurodegenerative diseases, including Alzheimer's disease.