title: The novel Tau mutation G335S: clinical, neuropathological and molecular characterization.
abstract: Mutations in Tau cause the inherited neurodegenerative disease, frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Known coding region mutations cluster in the microtubule-binding region, where they alter the ability of tau to promote microtubule assembly. Depending on the tau isoforms, this region consists of three or four imperfect repeats of 31 or 32 amino acids, each of which contains a characteristic and invariant PGGG motif. Here, we report the novel G335S mutation, which changes the PGGG motif of the third tau repeat to PGGS, in an individual who developed social withdrawal, emotional bluntness and stereotypic behavior at age 22, followed by disinhibition, hyperorality and ideomotor apraxia. Abundant tau-positive inclusions were present in neurons and glia in the frontotemporal cortex, hippocampus and brainstem. Sarkosyl-insoluble tau showed paired helical and straight filaments, as well as more irregular rope-like filaments. The pattern of pathological tau bands was like that of Alzheimer disease. Experimentally, the G335S mutation resulted in a greatly reduced ability of tau to promote microtubule assembly, while having no significant effect on heparin-induced assembly of recombinant tau into filaments.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive MS A138, Indianapolis, IN, 46202, USA. bghetti@iupui.edu
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spina
authors.forename: Jill R
authors.initials: JR
authors.lastname: Murrell
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yoshida
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Niamh
authors.initials: N
authors.lastname: Bermingham
authors.forename: Brian
authors.initials: B
authors.lastname: Sweeney
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Dlouhy
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Crowther
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.forename: Catherine
authors.initials: C
authors.lastname: Keohane
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis / Q000379:methods; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005998:Glycine / Q000235:genetics*; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012694:Serine / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D016875:tau Proteins; D012694:Serine; D005998:Glycine