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The basis of clinicopathological heterogeneity in TDP-43 proteinopathy

Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U),...

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Autores principales: Kawakami, Ito, Arai, Tetsuaki, Hasegawa, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800885/
https://www.ncbi.nlm.nih.gov/pubmed/31555895
http://dx.doi.org/10.1007/s00401-019-02077-x
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author Kawakami, Ito
Arai, Tetsuaki
Hasegawa, Masato
author_facet Kawakami, Ito
Arai, Tetsuaki
Hasegawa, Masato
author_sort Kawakami, Ito
collection PubMed
description Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. The clinical phenotypes of ALS and FTLD-TDP (FTLD with abnormal intracellular accumulations of TDP-43) correlate with characteristic distribution patterns of the underlying pathology across specific brain regions with disease progression. Recent studies support the idea that pathological protein spreads from neuron to neuron via axonal transport in a hierarchical manner. However, little is known to date about the basis of the selective cellular and regional vulnerability, although the information would have important implications for the development of targeted and personalized therapies. Here, we aim to summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and their relationship to clinical phenotypes for the underlying selective neuronal and regional susceptibilities. Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research.
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spelling pubmed-68008852019-11-01 The basis of clinicopathological heterogeneity in TDP-43 proteinopathy Kawakami, Ito Arai, Tetsuaki Hasegawa, Masato Acta Neuropathol Review Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. The clinical phenotypes of ALS and FTLD-TDP (FTLD with abnormal intracellular accumulations of TDP-43) correlate with characteristic distribution patterns of the underlying pathology across specific brain regions with disease progression. Recent studies support the idea that pathological protein spreads from neuron to neuron via axonal transport in a hierarchical manner. However, little is known to date about the basis of the selective cellular and regional vulnerability, although the information would have important implications for the development of targeted and personalized therapies. Here, we aim to summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and their relationship to clinical phenotypes for the underlying selective neuronal and regional susceptibilities. Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research. Springer Berlin Heidelberg 2019-09-26 2019 /pmc/articles/PMC6800885/ /pubmed/31555895 http://dx.doi.org/10.1007/s00401-019-02077-x Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Review
Kawakami, Ito
Arai, Tetsuaki
Hasegawa, Masato
The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
title The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
title_full The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
title_fullStr The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
title_full_unstemmed The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
title_short The basis of clinicopathological heterogeneity in TDP-43 proteinopathy
title_sort basis of clinicopathological heterogeneity in tdp-43 proteinopathy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800885/
https://www.ncbi.nlm.nih.gov/pubmed/31555895
http://dx.doi.org/10.1007/s00401-019-02077-x
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