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标题：Molecular, functional, and pathological aspects of TDP-43 fragmentation
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作者：Deepak Chhangani ; Alfonso Martín-Peña ; Diego E. Rincon-Limas 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：5
页码：1-17
DOI：10.1016/j.isci.2021.102459
语种：English
出版社：Elsevier
摘要：SummaryTransactive 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.Graphical abstractDisplay OmittedHighlights•TDP-43 fragments may contribute to loss- and gain-of-function mechanisms•Proteolysis as well as alternative splicing can lead to TDP-43 truncation•Several neurological conditions beyond the ALS/FTLD spectrum display TDP-43 fragments•The precise biological and pathological roles of TDP-43 fragments are unknownBiological sciences; Molecular physiology; Molecular biology; Molecular interaction;