ALS and FTLD: two faces of TDP‐43 proteinopathy

<jats:p>Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA‐binding protein 43 (TDP‐43), encoded by the <jats:italic>TARDBP</jats:italic> gene, has been identified as the major pathological protein of FTLD with ubiquitin‐immunoreactive (ub‐ir) inclusions (FTLD‐U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the <jats:italic>TARDBP</jats:italic> gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP‐43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD‐U, however, are now known to have mutations in the <jats:italic>progranulin</jats:italic> (<jats:italic>GRN</jats:italic>) gene, but granulin is not a component of the TDP‐43‐ and ub‐ir inclusions. Further, TDP‐43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD‐U entities with TDP‐43 proteinopathy include: FTLD‐U with <jats:italic>valosin‐containing protein</jats:italic> (<jats:italic>VCP</jats:italic>) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3‐linked dementia, FTLD‐U with <jats:italic>chromatin modifying protein 2B</jats:italic> (<jats:italic>CHMP2B</jats:italic>) mutation, has ub‐ir, TDP‐43‐negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP‐43 proteinopathies including: FTLD‐U, FTLD‐U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics.</jats:p>