Mitochondrial LonP1 protease is implicated in the degradation of unstable Parkinson disease-associated DJ-1/PARK 7 missense mutants.

DJ-1/PARK7 mutations are linked with familial forms of early onset Parkinson disease (PD). We have studied the degradation of untagged DJ-1 WT and missense mutants in mouse embryomic fibroblasts obtained from DJ-1 null mice, an approach closer to the situation in patients carrying homozygous mutations. The results showed that the mutants: L10P, M26I, A107P, P158DEL, L166P, E163K and L172Q are unstable proteins, while A39S, E64D, R98Q, A104T, D149A, A171S, K175E and A179T are as stable as the DJ-1 WT. Inhibition of proteasomal and autophagic-lysosomal pathways had little effect on their degradation. Immunofluorescence and biochemical fractionation studies indicated that M26I, A107P, P158DEL, L166P, E163K and L172Q mutants associate with mitochondria. Silencing of mitochondrial matrix protease LonP1 produced a strong reduction of the degradation of those mitochondrialy associated DJ-1 mutants, but not of mutant L10P. These results demonstrated a mitochondrial pathway of degradation of those DJ-1 missense mutants implicated in PD pathogenesis.