A new mitochondrial gene causing neurodegeneration and amyloid deposition in the brain
In this study we established for the first time a direct link between an altered mitochondrial function and amyloid neurodegeneration.
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In this collaborative study, we described the first family with a (recessive) pathological mutation in the gene encoding PITRM1, the mitochondrial matrix metallopeptidase that digests mitochondrial targeting sequences after cleavage by the mitochondrial matrix peptidase. The PITRM1 mutation was associated with a slowly progressive neurodegenerative condition characterized by mild mental retardation, spinocerebellar ataxia with cerebellar atrophy and psychosis.
We confirmed the pathogenicity of the mutation by investigating mutant and RNAi cells, and a yeast model (the yeast ortholog is CYM1). In vitro assays carried out on the recombinant protein expressed in E. coli, led us to conclude that the mutation causes severe protein instability mimicking a condition of haploinsufficiency. Investigations of a Pitrm1-/+ mouse model (the Pitrm1-/- individuals are embryonic lethal), also showed reduced Pitrm1 protein in different tissues and the animals developed a progressive neurological syndrome characterized by ataxia, behavioural impairment and abnormal bioenergetics parameters in vivo.
Interestingly, neuropathological investigation of these animals revealed the accumulation of Amyloid Precursor Protein and amyloid beta (Aβ) deposits, similar to the amyloid plaques seen in Alzheimer's disease brains (see figure). The accumulation of Aβ supports the hypothesis that PITRM1 is involved in the quantitative digestion of a fraction of Aβ and that this protein product is indeed contained within mitochondria. This observation has been controversial and our findings confirm this for the first time in a mammalian model.
This work was a collaboration between groups from Norway (Bergen - MMN & Center for Medical Genetics and Molecular Medicine; Førde), UK (MBU, Cambridge), Italy (Rome, Parma) and Sweden (Stockholm)