Defective PITRM1 mitochondrial peptidase is associated with A amyloidotic neurodegeneration
Number of Authors: 21
2016 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 8, no 3, 176-190 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2016. Vol. 8, no 3, 176-190 p.
amyloid beta, mitochondrial targeting sequence, mitochondrial disease, neurodegeneration, pitrilysin 1
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:su:diva-129217DOI: 10.15252/emmm.201505894ISI: 000372151100002OAI: oai:DiVA.org:su-129217DiVA: diva2:931424