Loss of DJ-1 protein stability and cytoprotective function by Parkinson's disease-associated proline-158 deletion.

DJ-1 is a ubiquitous protein regulating cellular viability. Recessive mutations in the PARK7/DJ-1 gene are linked to Parkinson's disease (PD). Although the most dramatic L166P point mutation practically eliminates DJ-1 protein and function, the effects of other PD-linked mutations are subtler. Here, we investigated two recently described PD-associated DJ-1 point mutations, the A179T substitution and the P158 in-frame deletion. [A179T]DJ-1 protein was as stable as wild-type [wt]DJ-1, but the P158 mutant protein was less stable. In accord with the notion that dimer formation is essential for DJ-1 protein stability, [P158]DJ-1 was impaired in dimer formation. Similar to our previous findings for [M26I]DJ-1, [P158]DJ-1 bound aberrantly to apoptosis signal-regulating kinase 1. Thus, the PD-associated P158 mutation destabilizes DJ-1 protein and function. As there is also evidence for an involvement of DJ-1 in multiple system atrophy, a PD-related -synucleinopathy characterized by oligodendroglial cytoplasmic inclusions, we studied an oligodendroglial cell line stably expressing -synuclein. -Synuclein aggregate dependent microtubule retraction upon co-transfection with tubulin polymerization-promoting protein p25 was ameliorated by [wt]DJ-1. In contrast, DJ-1 mutants including P158 failed to protect in this system, where we found evidence of apoptosis signal-regulating kinase 1 (ASK1) involvement. In conclusion, the P158 point mutation may contribute to neurodegeneration by protein destabilization and hence loss of DJ-1 function.