Fatty acid nitroalkene inhibition of LRRK2 hyperactivation and induction of neuroprotection in a model of Parkinson’s disease

The pathogenic events in Parkinson’s disease (PD), responsible for the loss of dopaminergic neurons and motor function, stem from interacting environmental, genetic, and inflammatory factors. These induce leucine-rich-repeat kinase 2 (LRRK2) hyperactivation, lipid oxidation, protein aggregation and suppression of Nrf2-regulated antioxidant and tissue repair gene expression programs. Although current therapies provide symptomatic relief, no FDA-approved disease-modifying strategies are available yet.

In a chronic rotenone rat model of PD, administration of the fatty acid nitroalkene 10-nitro-octadec-9-enoic acid (10-NO2-OA) induced biochemical responses that reduced neuronal damage, nigrostriatal degeneration and motor impairment. Specifically, 10-NO2-OA inhibited LRRK2 activity and reduced both net 4-hydroxynonenal (4-HNE) levels and the accumulation of LRRK2-hyperactivating 4-HNE-LRRK2 adducts in the substantia nigra pars compacta (SNpc). A click chemistry-based strategy in rat brain homogenates and HEK293 cells carrying Cys2024 and Cys2025 LRRK2 mutations confirmed that 10-NO2-OA induced the post-translational modification (PTM) of LRRK2. 10-NO2-OA also induced 4-HNE detoxification via Nrf2-dependent upregulation of aldehyde dehydrogenase 1A1 (ALDH1A1) expression and activity in the SNpc.

ALDH1A1 knockdown in primary ventral midbrain rat neurons abolished the impact of 10-NO2-OA on rotenone-induced 4-HNE accumulation. These results indicate that 10-NO2-OA exerts neuroprotective effects by both directly inhibiting LRRK2 and by limiting its hyperactivation through ALDH1A1 expression and the resultant acceleration of 4-HNE detoxification. These findings suggest 10-NO2-OA may be a potential disease-modifying agent for treating PD.

This work was financially supported by NIH grants, R01-HL162787 (M.F.), R01-HL132550 (B.A.F.), R01-NS126203-01A1 (R.D.M.), R01-NS095387 (T.G.) and R01-NS100744 (T.G.), the American Parkinson Disease Association (T.G.) and the Michael J. Fox Foundation for Parkinson’s Research (T.G.). These authors contributed equally: Marco Fazzari, Roberto Di Maio.

These authors contributed equally: Ahssan Sekandari, Macy Stoddard. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA Marco Fazzari, Ahssan Sekandari, Ese S. Freeman & Roberto Di Maio Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh, Pittsburgh, PA, USA Macy Stoddard, Christine Odoux, Isabella Sanders, Sandra Castro, Timothy Greenamyre & Roberto Di Maio Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA Aging Institute, University of Pittsburgh, Pittsburgh, PA, USA Correspondence to Marco Fazzari or Roberto Di Maio.

M.F., F.J.S., and B.A.F. acknowledge a competing financial interest in Creegh Pharmaceuticals Inc. The remaining authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.