title: ALS and FTLD: two faces of TDP-43 proteinopathy.
abstract: 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 TARDBP 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 TARDBP 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 progranulin (GRN) 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 valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) 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.
authors.affiliation: Institute for Medical Research and Occupational Health, Zagreb, Croatia.
authors.forename: R M
authors.initials: RM
authors.lastname: Liscic
authors.forename: L T
authors.initials: LT
authors.lastname: Grinberg
authors.forename: J
authors.initials: J
authors.lastname: Zidar
authors.forename: M A
authors.initials: MA
authors.lastname: Gitcho
authors.forename: N J
authors.initials: NJ
authors.lastname: Cairns
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003704:Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans
chemical_list: D004268:DNA-Binding Proteins