Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders

Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A...

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Main Authors:	Janssens, Jonathan, Van Broeckhoven, Christine
Format:	Online
Language:	English
Published:	Oxford University Press 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782069/

id	pubmed-3782069
recordtype	oai_dc
spelling	pubmed-37820692013-09-24 Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders Janssens, Jonathan Van Broeckhoven, Christine Reviews Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A direct causal link with TDP-43 brain proteinopathy was provided by the identification of pathogenic mutations in TARDBP, the gene encoding TDP-43, in ALS families. However, TDP-43 proteinopathy has also been observed in carriers of mutations in several other genes associated with both ALS and FTLD demonstrating a key role for TDP-43 in neurodegeneration. To date, and despite substantial research into the biology of TDP-43, its functioning in normal brain and in neurodegeneration processes remains largely elusive. Nonetheless, breakthroughs using cellular and animal models have provided valuable insights into ALS and FTLD pathogenesis. Accumulating evidence has redirected the research focus towards a major role for impaired RNA metabolism and protein homeostasis. At the same time, the concept that toxic TDP-43 protein aggregates promote neurodegeneration is losing its credibility. This review aims at highlighting and discussing the current knowledge on TDP-43 driven pathomechanisms leading to neurodegeneration as observed in TDP-43 proteinopathies. Based on the complexity of the associated neurological diseases, a clear understanding of the essential pathological modifications will be crucial for further therapeutic interventions. Oxford University Press 2013-10-15 2013-07-29 /pmc/articles/PMC3782069/ /pubmed/23900071 http://dx.doi.org/10.1093/hmg/ddt349 Text en © The Author 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Janssens, Jonathan Van Broeckhoven, Christine
spellingShingle	Janssens, Jonathan Van Broeckhoven, Christine Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders
author_facet	Janssens, Jonathan Van Broeckhoven, Christine
author_sort	Janssens, Jonathan
title	Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders
title_short	Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders
title_full	Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders
title_fullStr	Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders
title_full_unstemmed	Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders
title_sort	pathological mechanisms underlying tdp-43 driven neurodegeneration in ftld–als spectrum disorders
description	Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A direct causal link with TDP-43 brain proteinopathy was provided by the identification of pathogenic mutations in TARDBP, the gene encoding TDP-43, in ALS families. However, TDP-43 proteinopathy has also been observed in carriers of mutations in several other genes associated with both ALS and FTLD demonstrating a key role for TDP-43 in neurodegeneration. To date, and despite substantial research into the biology of TDP-43, its functioning in normal brain and in neurodegeneration processes remains largely elusive. Nonetheless, breakthroughs using cellular and animal models have provided valuable insights into ALS and FTLD pathogenesis. Accumulating evidence has redirected the research focus towards a major role for impaired RNA metabolism and protein homeostasis. At the same time, the concept that toxic TDP-43 protein aggregates promote neurodegeneration is losing its credibility. This review aims at highlighting and discussing the current knowledge on TDP-43 driven pathomechanisms leading to neurodegeneration as observed in TDP-43 proteinopathies. Based on the complexity of the associated neurological diseases, a clear understanding of the essential pathological modifications will be crucial for further therapeutic interventions.
publisher	Oxford University Press
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782069/
_version_	1612013970795790336

Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD–ALS spectrum disorders

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