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 P158Δ in-frame deletion. [A179T]DJ-1 protein was as stable as wild-type [wt]DJ-1, but the P158Δ mutant protein was less stable. In accord with the notion that dimer formation is essential for DJ-1 protein stability, [P158Δ]DJ-1 was impaired in dimer formation. Similar to our previous findings for [M26I]DJ-1, [P158Δ]DJ-1 bound aberrantly to apoptosis signal-regulating kinase 1. Thus, the PD-associated P158Δ 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 α-synucleinopathy characterized by oligodendroglial cytoplasmic inclusions, we studied an oligodendroglial cell line stably expressing α-synuclein. α-Synuclein aggregate dependent microtubule retraction upon co-transfection with tubulin polymerization-promoting protein p25α was ameliorated by [wt]DJ-1. In contrast, DJ-1 mutants including P158Δ failed to protect in this system, where we found evidence of apoptosis signal-regulating kinase 1 (ASK1) involvement. In conclusion, the P158Δ point mutation may contribute to neurodegeneration by protein destabilization and hence loss of DJ-1 function. © 2012 International Society for Neurochemistry.

Citation

Emmy H Rannikko, Louise Buur Vesterager, Jafar H A Shaik, Stephanie S Weber, Elena M Cornejo Castro, Karina Fog, Poul H Jensen, Philipp J Kahle. Loss of DJ-1 protein stability and cytoprotective function by Parkinson's disease-associated proline-158 deletion. Journal of neurochemistry. 2013 Apr;125(2):314-27

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PMID: 23241025

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