title: Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.
abstract: Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. The pathogenicity of the mutation was tested in vitro, in mutant fibroblasts and skeletal muscle, and in a yeast model. A Pitrm1(+/-) heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Aβ-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aβ degradation and that impairment of its activity results in Aβ accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK.
authors.forename: Dario
authors.initials: D
authors.lastname: Brunetti
authors.affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Janniche
authors.initials: J
authors.lastname: Torsvik
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Pedro
authors.initials: P
authors.lastname: Teixeira
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.
authors.forename: Pawel
authors.initials: P
authors.lastname: Sztromwasser
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK.
authors.forename: Erika
authors.initials: E
authors.lastname: Fernandez-Vizarra
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Cerutti
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Reyes
authors.affiliation: Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome, Rome, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Preziuso
authors.affiliation: Department of Radiological, Oncological and Pathological Sciences Sapienza University of Rome, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: D'Amati
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Baruffini
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Goffrini
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Viscomi
authors.affiliation: Department of Life Sciences, University of Parma, Parma, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Boman
authors.affiliation: Department of Neurology, Førde Hospital, Førde, Norway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Telstad
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Glaser
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust, Cambridge, UK mdz21@mrc-mbu.cam.ac.uk laurence.bindoff@nevro.uib.no.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.affiliation: Department of Neurology, Haukeland University Hospital, Bergen, Norway Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway mdz21@mrc-mbu.cam.ac.uk laurence.bindoff@nevro.uib.no.
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D004195:Disease Models, Animal; D006651:Histocytochemistry; D006801:Humans; D008279:Magnetic Resonance Imaging; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D012441:Saccharomyces cerevisiae; D035781:Siblings
chemical_list: D016229:Amyloid beta-Peptides; D050505:Mutant Proteins; D008666:Metalloendopeptidases; C119694:PITRM1 protein, human
keywords: amyloid beta; mitochondrial disease; mitochondrial targeting sequence; neurodegeneration; pitrilysin 1