Defective PITRM1 mitochondrial peptidase is associated with Aß amyloidotic neurodegeneration.
EMBO Mol Med
; 8(3): 176-90, 2016 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-26697887
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 (Aß). 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 Aß-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aß degradation and that impairment of its activity results in Aß accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Metaloendopeptidases
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Peptídeos beta-Amiloides
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Doenças Neurodegenerativas
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
EMBO Mol Med
Ano de publicação:
2016
Tipo de documento:
Article