What is the key player in TDP‐43 pathology in ALS: Disappearance from the nucleus or inclusion formation in the cytoplasm?

Abstract

AbstractC9ORF72 and the 43 kDa TAR DNA‐binding protein (TDP‐43) are key molecules in the development of TDP‐43 pathology in amyotrophic lateral sclerosis (ALS). The hexanucleotide repeat expansion in C9ORF72 also leads to frontotemporal lobar degeneration, whereas mutation of TARDBP mainly causes ALS, indicating that TDP‐43 plays a more fundamental role in the development of ALS. In tissues affected with ALS, TDP‐43 is dislocated from the nucleus, forms cytoplasmic inclusions, and is phosphorylated and truncated. Accumulating evidence suggests that the disappearance of TDP‐43 from the nucleus precedes inclusion formation, indicating that its disappearance from the nucleus is crucial in the development of TDP‐43 pathology. Alterations in the quality and quantity of TDP‐43 might result in the disappearance of TDP‐43 from the nucleus. Regarding quality, phosphorylation and truncation of TDP‐43 is not necessary for its disappearance from the nucleus or for inclusion formation. Although it has been speculated that studies of TDP‐43 harboring ALS‐associated mutations are useful for understanding the molecular pathogenesis of sporadic ALS, the functional and biochemical differences between mutated and wild‐type TDP‐43 remain unclear. Regarding quantity, an increased amount of TDP‐43 is an attractive hypothesis as it has been shown that increased amounts of TDP‐43 are toxic. Moreover, several reports have suggested that increased levels of TDP‐43 are found in sporadic ALS as well as in ALS with TDP‐43 mutations. However, these findings remain controversial. Increased understanding of the mechanisms responsible for regulating TDP‐43 will provide a basis for determining the molecular pathogenesis of ALS.