Does a loss of TDP-43 function cause neurodegeneration?
In 2006, TAR-DNA binding protein 43 kDa (TDP-43) was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, 817 LRB, Worcester, MA 01605, USA. Zuoshang.xu@umassmed.edu
Zuo-Shang
ZS
Xu
D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*
D004268:DNA-Binding Proteins