title: [Frontotemporal dementia (FTD) and genetic mutations including progranulin gene].
abstract: Research on familial frontotemporal lobar degeneration (FTLD) has led to the discovery of disease-causing genes: microtubule-associated protein tau (MAPT), progranulin (PGRN) and valosin-containing protein (VCP). TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as a major component of tau-negative ubiquitin-positive inclusions in familial and sporadic FTLD and amyotrophic lateral sclerosis (ALS), which are now referred to as TDP-43 proteinopathy. Recent findings of mutations in TDP-43 gene in familial and sporadic ALS cases confirm the pathogenetic role for TDP-43 in neurodegeneration. TDP-43 proteinopathies have been classified into 4 pathological subtypes. Type 1 is characterized by numerous dystrophic neurites (DNs), Type 2 has numerous neuronal cytoplasmic inclusions (NCIs), Type 3 has NCIs and DNs and Type 4 has neuronal intranuclear inclusions (NIIs) and DNs. There is a close relationship between such pathological subtypes of TDP-43 proteinopathy and the immunoblot pattern of C-terminal fragments of accumulated TDP-43. These results parallel our earlier findings of differing C-terminal tau fragments in progressive supranuclear palsy and corticobasal degeneration, despite identical composition of tau isoforms. Taken together, these results suggest that elucidating the mechanism of C-terminal fragment origination may shed light on the pathogenesis of several neurodegenerative disorders involving TDP-43 proteinopathy and tauopathy.
authors.affiliation: Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research.
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Masugi
authors.initials: M
authors.lastname: Nishihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Kametani
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.forename: Mitsuya
authors.initials: M
authors.lastname: Morita
authors.forename: Imaharu
authors.initials: I
authors.lastname: Nakano
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Oda
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003704:Dementia / Q000145:classification / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D000077153:Progranulins; D000074405:Valosin Containing Protein; D016875:tau Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D016875:tau Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein