Defective PITRM1 Mitochondrial Peptidase is Associated with Aβ Amyloidotic Neurodegeneration

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2015 Dec 25

PMID 26697887

Citations 40

Authors

Dario Brunetti

Janniche Torsvik

Cristina Dallabona

Pedro Teixeira

Pawel Sztromwasser

Erika Fernandez-Vizarra

Raffaele Cerutti

Aurelio Reyes

Carmela Preziuso

Giulia dAmati

Enrico Baruffini

Paola Goffrini

Carlo Viscomi

Ileana Ferrero

Helge Boman

Wenche Telstad

Stefan Johansson

Elzbieta Glaser

Per M Knappskog

Massimo Zeviani

Laurence A Bindoff

Affiliations

Soon will be listed here.

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 (Aβ). 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 Aβ-positive amyloid deposits. Our results show that PITRM1 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.

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