Dataset Information

Molecular, functional, and pathological aspects of TDP-43 fragmentation.

ABSTRACT: Transactive response DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in transcriptional regulation and RNA processing. It is linked to sporadic and familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is predominantly nuclear, but it translocates to the cytoplasm under pathological conditions. Cytoplasmic accumulation, phosphorylation, ubiquitination and truncation of TDP-43 are the main hallmarks of TDP-43 proteinopathies. Among these processes, the pathways leading to TDP-43 fragmentation remain poorly understood. We review here the molecular and biochemical properties of several TDP-43 fragments, the mechanisms and factors mediating their production, and their potential role in disease progression. We also address the presence of TDP-43 C-terminal fragments in several neurological disorders, including Alzheimer's disease, and highlight their respective implications. Finally, we discuss features of animal models expressing TDP-43 fragments as well as recent therapeutic strategies to approach TDP-43 truncation.

SUBMITTER: Chhangani D

PROVIDER: S-EPMC8113996 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular, functional, and pathological aspects of TDP-43 fragmentation.

Chhangani Deepak D Martín-Peña Alfonso A Rincon-Limas Diego E DE

iScience 20210421 5

Transactive response DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in transcriptional regulation and RNA processing. It is linked to sporadic and familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is predominantly nuclear, but it translocates to the cytoplasm under pathological conditions. Cytoplasmic accumulation, phosphorylation, ubiquitination and truncation of TDP-43 are the main hallmarks of TDP-43 proteinopathies. Among these proces ...[more]

PMID: 34013172

Similar Datasets

Project description:Tar DNA binding protein 43 (TDP-43) is the major component of pathological deposits in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in amyotrophic lateral sclerosis (ALS). It has been reported that TDP-43 transgenic mouse models expressing human TDP-43 wild-type or ALS-associated mutations recapitulate certain ALS and FTLD pathological phenotypes. Of note, expression of human TDP-43 (hTDP-43) reduces the levels of mouse Tdp-43 (mTdp-43). However, it remained unclear whether the mechanisms through which TDP-43 induces ALS or FTLD-like pathologies resulted from a reduction in mTdp-43, an increase in hTDP-43, or a combination of both. In elucidating the role of mTdp-43 and hTDP-43 in hTDP-43 transgenic mice, we observed that reduction of mTdp-43 in non-transgenic mice by intraventricular brain injection of AAV1-shTardbp leads to a dramatic increase in the levels of splicing variants of mouse sortilin 1 and translin. However, the levels of these two abnormal splicing variants are not increased in hTDP-43 transgenic mice despite significant downregulation of mTdp-43 in these mice. Moreover, further downregulation of mTdp-43 in hTDP-43 hemizygous mice, which are asymptomatic, to the levels equivalent to that of mTdp-43 in hTDP-43 homozygous mice does not induce the pathological phenotypes observed in the homozygous mice. Lastly, the number of dendritic spines and the RNA levels of TDP-43 RNA targets critical for synapse formation and function are significantly decreased in symptomatic homozygous mice. Together, our findings indicate that mTdp-43 downregulation does not lead to a loss of function mechanism or account for the pathological phenotypes observed in hTDP-43 homozygous mice because hTDP-43 compensates for the reduction, and associated functions of mTdp-43. Rather, expression of hTDP-43 beyond a certain threshold leads to abnormal metabolism of TDP-43 RNA targets critical for neuronal structure and function, which might be responsible for the ALS or FTLD-like pathologies observed in homozygous hTDP-43 transgenic mice.

Dataset Information

Molecular, functional, and pathological aspects of TDP-43 fragmentation.

Publications

Molecular, functional, and pathological aspects of TDP-43 fragmentation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets