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Defective PITRM1 mi...
Defective PITRM1 mitochondrial peptidase is associated with A amyloidotic neurodegeneration
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Brunetti, Dario (author)
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Torsvik, Janniche (author)
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Dallabona, Cristina (author)
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- Teixeira, Pedro (author)
- Stockholms universitet,Institutionen för biokemi och biofysik
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Sztromwasser, Pawel (author)
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Fernandez-Vizarra, Erika (author)
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Cerutti, Raffaele (author)
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Reyes, Aurelio (author)
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Preziuso, Carmela (author)
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D'Amati, Giulia (author)
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Baruffini, Enrico (author)
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Goffrini, Paola (author)
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Viscomi, Carlo (author)
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Ferrero, Ileana (author)
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Boman, Helge (author)
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Telstad, Wenche (author)
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Johansson, Stefan (author)
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- Glaser, Elzbieta (author)
- Stockholms universitet,Institutionen för biokemi och biofysik
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Knappskog, Per M. (author)
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Zeviani, Massimo (author)
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Bindoff, Laurence A. (author)
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(creator_code:org_t)
- 2015-12-23
- 2016
- English.
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In: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 8:3, s. 176-190
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https://doi.org/10.1...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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 (A). 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 invitro, 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 A-positive amyloid deposits. Our results show that PITRM1 is responsible for significant A degradation and that impairment of its activity results in A accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- amyloid beta
- mitochondrial targeting sequence
- mitochondrial disease
- neurodegeneration
- pitrilysin 1
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Brunetti, Dario
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Torsvik, Jannich ...
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Dallabona, Crist ...
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Teixeira, Pedro
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Sztromwasser, Pa ...
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Fernandez-Vizarr ...
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show more...
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Cerutti, Raffael ...
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Reyes, Aurelio
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Preziuso, Carmel ...
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D'Amati, Giulia
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Baruffini, Enric ...
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Goffrini, Paola
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Viscomi, Carlo
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Ferrero, Ileana
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Boman, Helge
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Telstad, Wenche
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Johansson, Stefa ...
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Glaser, Elzbieta
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Knappskog, Per M ...
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Zeviani, Massimo
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Bindoff, Laurenc ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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EMBO Molecular M ...
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Stockholm University