Defective PITRM 1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration

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 (Ab). 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 +/À heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Ab-positive amyloid deposits. Our results show that PITRM1 is responsible for significant Ab degradation and that impairment of its activity results in Ab accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.

Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy

“…In family A, intellectual disability is moderate, and cerebellar dysfunction is much more severe, with significant ataxia from early childhood, and severe cerebellar atrophy on brain imaging at age 9 years. This clinical presentation seems comparable to that observed in two adult siblings from a previously reported Norwegian family, much older than the patients described in this study 4. In family B, the children (aged 13 and 4 years) presented with mild intellectual disability.…”

“…The older child also had tremor and mild ataxia from age 2 years, with normal brain imaging at age 12 years. This may be compatible with an age-dependent phenotype similar to the previously reported Norwegian family 4. Families A and B share the same mutation, and the clinical variability may be explained by the X-chromosome rearrangement, found only in family A and leading to significant X-chromosome skewing in the carrier females.…”

“…cym1S882T and cym1S882M mutant alleles were constructed, cloned and inserted, together with CYM1 WT allele and the empty plasmid pFL38, in strain W303-1B cym1Δ as previously described 4. Oligonucleotides for plasmid construction are listed in supplementary table 1.…”

“…Mutations in >45 genes are known to cause ARCA, yet the molecular causes of ARCA in many patients remain unknown 3. Recently, homozygosity for PITRM1 R183Q was described in a Norwegian brother and sister in their late 60s with recessive spinocerebellar ataxia 4. Both had mild mental retardation in childhood and gradually developed spinocerebellar ataxia and obsessional behaviour with psychotic episodes.…”

“…In vitro, its catalytic activity was comparable to wild-type protein. In a yeast model system, the R183Q substitution resulted in lower mitochondrial oxygen consumption and cytochrome content and reduced capacity to degrade Aβ 4. A recent study showed that the structural and electrostatic properties of the conserved strand-loop-strand motif containing PITRM1  residue R183 are critically important for PITRM1 function.…”