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Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear...

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Autores principales: Riku, Yuichi, Seilhean, Danielle, Duyckaerts, Charles, Boluda, Susana, Iguchi, Yohei, Ishigaki, Shinsuke, Iwasaki, Yasushi, Yoshida, Mari, Sobue, Gen, Katsuno, Masahisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068029/
https://www.ncbi.nlm.nih.gov/pubmed/33917673
http://dx.doi.org/10.3390/ijms22083843
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author Riku, Yuichi
Seilhean, Danielle
Duyckaerts, Charles
Boluda, Susana
Iguchi, Yohei
Ishigaki, Shinsuke
Iwasaki, Yasushi
Yoshida, Mari
Sobue, Gen
Katsuno, Masahisa
author_facet Riku, Yuichi
Seilhean, Danielle
Duyckaerts, Charles
Boluda, Susana
Iguchi, Yohei
Ishigaki, Shinsuke
Iwasaki, Yasushi
Yoshida, Mari
Sobue, Gen
Katsuno, Masahisa
author_sort Riku, Yuichi
collection PubMed
description Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations.
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spelling pubmed-80680292021-04-25 Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration Riku, Yuichi Seilhean, Danielle Duyckaerts, Charles Boluda, Susana Iguchi, Yohei Ishigaki, Shinsuke Iwasaki, Yasushi Yoshida, Mari Sobue, Gen Katsuno, Masahisa Int J Mol Sci Review Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations. MDPI 2021-04-08 /pmc/articles/PMC8068029/ /pubmed/33917673 http://dx.doi.org/10.3390/ijms22083843 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Riku, Yuichi
Seilhean, Danielle
Duyckaerts, Charles
Boluda, Susana
Iguchi, Yohei
Ishigaki, Shinsuke
Iwasaki, Yasushi
Yoshida, Mari
Sobue, Gen
Katsuno, Masahisa
Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
title Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
title_full Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
title_fullStr Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
title_full_unstemmed Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
title_short Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration
title_sort pathway from tdp-43-related pathology to neuronal dysfunction in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068029/
https://www.ncbi.nlm.nih.gov/pubmed/33917673
http://dx.doi.org/10.3390/ijms22083843
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