title: Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology.
abstract: Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal system. Consistent with these findings, CHMP2B mutation patient brains contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD.
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Clayton
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mizielinska
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Edgar
authors.affiliation: Neurogenetics Research Laboratory, Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Troels Tolstrup
authors.initials: TT
authors.lastname: Nielsen
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Norona
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Miranda
authors.initials: M
authors.lastname: Robbins
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Hana
authors.initials: H
authors.lastname: Damirji
authors.affiliation: Laboratory for Experimental Neuropathology, Department of Pathology, Randers Hospital, 8930, Randers NØ, Denmark.|Institute of Clinical Medicine, Aarhus University, 8000, Aarhus C, Denmark.
authors.forename: Ida E
authors.initials: IE
authors.lastname: Holm
authors.affiliation: Memory Clinic, Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Johannsen
authors.affiliation: Neurogenetics Research Laboratory, Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|Memory Clinic, Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|Department of Cellular and Molecular Medicine, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jørgen E
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: MRC Prion Unit, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Asante
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.|MRC Prion Unit, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. a.isaacs@prion.ucl.ac.uk.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization
chemical_list: C503812:CHMP2B protein, human; C525139:CHMP2B protein, mouse; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins
keywords: CHMP2B; ESCRT; FTD; Lysosomal storage disorder; Lysosome