Antioxidants inhibit neuronal toxicity in Parkinson's disease-linked LRRK2

Ann Clin Transl Neurol. 2016 Mar 2;3(4):288-94. doi: 10.1002/acn3.282. eCollection 2016 Apr.


Mutations in leucine-rich repeat kinase-2 are the most common cause of familial Parkinson's disease. The prevalent G2019S mutation increase oxidative, kinase and toxic activity and inhibit endogenous peroxidases. We initially screened a library of 84 antioxidants and identified seven phenolic compounds that inhibited kinase activity on leucine-rich repeat kinase-2 substrates. The representative antioxidants (piceatannol, thymoquinone, and esculetin) with strong kinase inhibitor activity, reduced loss in dopaminergic neurons, oxidative dysfunction, and locomotor defects in G2019S-expressing neuronal and Drosophila models compared to weak inhibitors. We provide proof of principle that natural antioxidants with dual antioxidant and kinase inhibitor properties could be useful for leucine-rich repeat kinase-2-linked Parkinson's disease.