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Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic...

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Autores principales: Asakawa, Kazuhide, Handa, Hiroshi, Kawakami, Koichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195926/
https://www.ncbi.nlm.nih.gov/pubmed/33709256
http://dx.doi.org/10.1007/s00018-021-03792-z
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author Asakawa, Kazuhide
Handa, Hiroshi
Kawakami, Koichi
author_facet Asakawa, Kazuhide
Handa, Hiroshi
Kawakami, Koichi
author_sort Asakawa, Kazuhide
collection PubMed
description Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In most ALS cases, cytoplasmic TDP-43 aggregation occurs in the absence of mutations in the coding sequence of TARDBP. Thus, a major challenge in ALS research is to understand the nature of pathological changes occurring in wild-type TDP-43 and to explore upstream events in intracellular and extracellular milieu that promote the pathological transition of TDP-43. Despite the inherent obstacles to analyzing TDP-43 dynamics in in vivo motor neurons due to their anatomical complexity and inaccessibility, recent studies using cellular and animal models have provided important mechanistic insights into potential links between TDP-43 and motor neuron vulnerability in ALS. This review is intended to provide an overview of the current literature on the function and regulation of TDP-43-containing RNP granules or membraneless organelles, as revealed by various models, and to discuss the potential mechanisms by which TDP-43 can cause selective vulnerability of motor neurons in ALS.
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spelling pubmed-81959262021-06-28 Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS Asakawa, Kazuhide Handa, Hiroshi Kawakami, Koichi Cell Mol Life Sci Review Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In most ALS cases, cytoplasmic TDP-43 aggregation occurs in the absence of mutations in the coding sequence of TARDBP. Thus, a major challenge in ALS research is to understand the nature of pathological changes occurring in wild-type TDP-43 and to explore upstream events in intracellular and extracellular milieu that promote the pathological transition of TDP-43. Despite the inherent obstacles to analyzing TDP-43 dynamics in in vivo motor neurons due to their anatomical complexity and inaccessibility, recent studies using cellular and animal models have provided important mechanistic insights into potential links between TDP-43 and motor neuron vulnerability in ALS. This review is intended to provide an overview of the current literature on the function and regulation of TDP-43-containing RNP granules or membraneless organelles, as revealed by various models, and to discuss the potential mechanisms by which TDP-43 can cause selective vulnerability of motor neurons in ALS. Springer International Publishing 2021-03-11 2021 /pmc/articles/PMC8195926/ /pubmed/33709256 http://dx.doi.org/10.1007/s00018-021-03792-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Review
Asakawa, Kazuhide
Handa, Hiroshi
Kawakami, Koichi
Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
title Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
title_full Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
title_fullStr Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
title_full_unstemmed Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
title_short Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
title_sort multi-phaseted problems of tdp-43 in selective neuronal vulnerability in als
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195926/
https://www.ncbi.nlm.nih.gov/pubmed/33709256
http://dx.doi.org/10.1007/s00018-021-03792-z
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