Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.
Knappskog, Per M
Bindoff, Laurence A
EMBO Molecular Medicine
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Brunetti, D., Torsvik, J., Dallabona, C., Teixeira, P., Sztromwasser, P., Fernandez-Vizarra, E., Cerutti, R., et al. (2016). Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.. EMBO Molecular Medicine, 8 (3), 176-190. https://doi.org/10.15252/emmm.201505894
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.
amyloid beta, mitochondrial disease, mitochondrial targeting sequence, neurodegeneration, pitrilysin 1, Amyloid beta-Peptides, Animals, Brain, Disease Models, Animal, Histocytochemistry, Humans, Magnetic Resonance Imaging, Metalloendopeptidases, Mice, Models, Biological, Muscle, Skeletal, Mutant Proteins, Mutation, Missense, Neurodegenerative Diseases, Saccharomyces cerevisiae, Siblings
Cariplo2011‐0526 ERCFP7‐322424 Swedish Research Council Helse Vest911810 Forening for muskelsyke Italian Ministry of HealthGR‐2010‐2306‐756
European Commission FP7 ERC Advanced Investigator Grants (AIG) (322424)
External DOI: https://doi.org/10.15252/emmm.201505894
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266260
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/