title: Antioxidants inhibit neuronal toxicity in Parkinson's disease-linked LRRK2.
abstract: 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.
authors.affiliation: Department of Neurology Singapore General Hospital 20 College Rd The Academia Discovery Tower Singapore 169856; Departments of Psychology and Pediatrics National University of Singapore Singapore.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Angeles
authors.affiliation: National Neuroscience Institute 11 Tan Tock Seng Singapore 308433.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ho
authors.affiliation: Department of Pharmacy National University of Singapore 21 Lower Kent Ridge Singapore 119077.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
authors.affiliation: National Neuroscience Institute 11 Tan Tock Seng Singapore 308433; Department of Physiology National University of Singapore 21 Lower Kent Ridge Singapore 119077; Duke-NUS Graduate Medical School 8 College Rd Singapore 169857.
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
authors.affiliation: Department of Neurology Singapore General Hospital 20 College Rd The Academia Discovery Tower Singapore 169856.
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Zhou
authors.affiliation: Department of Neurology Singapore General Hospital 20 College Rd The Academia Discovery Tower Singapore 169856; National Neuroscience Institute 11 Tan Tock Seng Singapore 308433; Duke-NUS Graduate Medical School 8 College Rd Singapore 169857.
authors.forename: Eng-King
authors.initials: EK
authors.lastname: Tan