TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies

Abstract

Given the critical role for TDP-43 in diverse neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), there has been a recent surge in efforts to understand the normal functions of TDP-43 and the molecular basis of dysregulation that occurs in TDP-43 proteinopathies. Here, we highlight recent findings examining TDP-43 molecular functions with particular emphasis on stress-mediated regulation of TDP-43 localization, putative downstream TDP-43 target genes and RNAs, as well as TDP-43 interacting proteins, all of which represent viable points of therapeutic intervention for ALS, FTLD-TDP and related proteinopathies. Finally, we review current mouse models of TDP-43 and discuss their similarities and potential relevance to human TDP-43 proteinopathies including ALS and FTLD-TDP.

Figure 1. Schematic of TDP-43 domain structure, ALS-associated mutations, and C-terminal fragments

TDP-43 protein contains a nuclear localization sequence (NLS), two RNA recognition motifs (RRMs), a nuclear export sequence (NES), and a glycine-rich domain that harbors the majority of ALS-associated genetic mutations. More than 35 ALS mutations have been identified, with the majority of mutations found within the glycine-rich region. Those mutations mentioned in the text are highlighted in the expanded view above. TDP-43 C-terminal truncated protein was identified within insoluble aggregates from FTLD-TDP brain tissue, and the precise fragment lengths identified are indicated.

Figure 2. Stress-granule mediated regulation of TDP-43 and its target RNAs

RNA bound TDP-43 complexes regulate global expression of genes required for diverse functions including auto-regulation of TDP-43 mRNA itself. Such regulation could potentially occur in the context of other RNA-binding proteins including FUS and RNA-associated factors (represented by X). Pathogenic ALS-associated mutations or conditions of oxidative insult promote recruitment of TDP-43 containing RNA complexes into stress granules via a TDP-43 Q/N rich C-terminal domain. TDP-43 is selectively recruited into specific stress granules (SGs) depending on the type of stress condition. Once recruited to SGs, TDP-43 may have a physiological role in the regulation of TDP-43-dependent RNAs during acute stress. However, pathological factors including prolonged stress or ageing, for example, could induce the formation of `pathological stress granules', representing persistent accumulation of coalesced SGs that form TDP-43 positive inclusions, characterized pathologically as TDP-43 aggregates in ALS and FTLD-TDP. The formation of pathological SGs could inhibit TDP-43 function via cytoplasmic sequestration of normal TDP-43 and/or initiate a toxic gain of function leading to mitochondrial damage and other neuronal dysfunctions.