title: Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases.
abstract: Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to alpha-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 3600 Spruce Street, Philadelphia, PA 19104-4283, USA. geserfel@mail.med.upenn.edu
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Lage
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003704:Dementia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins