TAR-DNA protein-43 (TDP-43) proteinopathy in amyotrophic lateral sclerosis

(1) TDP-43 is a DNA- and RNA-binding protein involved in RNA processing. Natively folded TDP-43, shown in the nucleus, regulates RNA splicing. As a nucleocytoplasmic shuttling protein, TDP-43 is also involved in cytoplasmic RNA processing including the stress granule response and RNA transport. (2) C9ORF72 mutation causes the sequestration of RNA-binding proteins, which impairs RNA processing. C9ORF72-mediated ALS also manifests with accumulation and aggregation of TDP-43. (3) MATR3, hnRNPA1, and hnRNPA2B1 mutations also impair RNA processing and induce TDP-43 proteinopathy, likely through direct binding interactions with TDP-43 which influence its folding and function. (4) FUS mutations are thought to cause ALS, independent of TDP-43 proteinopathy, via impaired processing of transcripts that may be common to those targeted by TDP-43. (5) Mislocalization of excess TDP-43 to the cytoplasm can be promoted by (6) TARDBP mutations and (7) environmental stressors, both of which also promote (8) TDP-43 fragmentation. (9) Cleaved and mislocalized TDP-43 species are prone to misfolding and aggregation, which is associated with the addition of phosphorylation and ubiquitin chains. (10) The ubiquitin proteasome system and autophagy ordinarily serve to maintain TDP-43 homeostasis; however, in ALS these protein degradation systems fail to prevent the accumulation of TDP-43, thus favoring the formation of large protein complexes called aggresomes. (11) Mutations in VCP, UBQLN2, and SQSTM1 can impair protein degradation. (12) Aberrant RNA processing, and particularly stress granule formation, may promote the aggregation of TDP-43. (13) Conversely, TDP-43 misfolding and aggregation impairs RNA processing function, and sequesters TDP-43 in a dominant-negative fashion. Strategies that prevent TDP-43 misfolding and/or enhance clearance of pathological TDP-43 have the potential to prevent RNA processing deficits and pathogenesis in the majority of ALS cases.