Title
Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLDALS spectrum disorders Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLDALS spectrum disorders
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Oxford ,
Subject
Chemistry
Biology
Human medicine
Source (journal)
Human molecular genetics. - Oxford
Volume/pages
22(2013) , p. 77-87
ISSN
0964-6906
ISI
000325340500012
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
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.
E-info
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