Loss of DJ‐1 protein stability and cytoprotective function by Parkinson's disease‐associated proline‐158 deletion |
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Authors: | Emmy H. Rannikko Louise Buur Vesterager Jafar H. A. Shaik Stephanie S. Weber Karina Fog Poul H. Jensen Philipp J. Kahle |
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Affiliation: | 1. Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Faculty of Medicine, University of Tübingen, , Germany;2. Department of Biomedicine, Faculty of Health Sciences, University of Aarhus, , Denmark;3. H. Lundbeck A/S, Department of Neurodegeneration, , Valby, Denmark;4. German Center for Neurodegenerative Diseases, , Tübingen, Germany |
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Abstract: | 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. |
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Keywords: | apoptosis signal‐regulating kinase 1 DJ‐1 multiple system atrophy Parkinson's disease protein stability synuclein |
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