Open AccessDefective PITRM 1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration
Author(s) -
Brunetti Dario,
Torsvik Janniche,
Dallabona Cristina,
Teixeira Pedro,
Sztromwasser Pawel,
FernandezVizarra Erika,
Cerutti Raffaele,
Reyes Aurelio,
Preziuso Carmela,
D'Amati Giulia,
Baruffini Enrico,
Goffrini Paola,
Viscomi Carlo,
Ferrero Ileana,
Boman Helge,
Telstad Wenche,
Johansson Stefan,
Glaser Elzbieta,
Knappskog Per M,
Zeviani Massimo,
Bindoff Laurence A
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505894
Subject(s) - neurodegeneration , proteostasis , ataxia , biology , missense mutation , mitochondrion , mutation , microbiology and biotechnology , biochemistry , medicine , neuroscience , gene , disease
Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 ( PITRM 1) 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 PITRM 1 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 PITRM 1 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.