| First Author | Brunetti D | Year | 2016 |
| Journal | EMBO Mol Med | Volume | 8 |
| Issue | 3 | Pages | 176-90 |
| PubMed ID | 26697887 | Mgi Jnum | J:236767 |
| Mgi Id | MGI:5807037 | Doi | 10.15252/emmm.201505894 |
| Citation | Brunetti D, et al. (2015) Defective PITRM1 mitochondrial peptidase is associated with Abeta amyloidotic neurodegeneration. EMBO Mol Med 8(3):176-90 |
| abstractText | 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 (Abeta). 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 Abeta-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Abeta degradation and that impairment of its activity results in Abeta accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration. |
