Fatty acid Nitroalkene inhibition of LRRK2 hyperactivation and oxidative stress in Parkinson's disease

Parkinson’s disease (PD) is the fastest-growing age-related movement disorder and lacks disease-modifying therapies. The disease's complex etiology involves convergent genetic, environmental, and inflammatory stresses that drive hyperactivation of leucine-rich repeat kinase 2 (LRRK2), suppression of Nrf2-dependent cytoprotective pathways, and accumulation of toxic aldehydes such as 4-hydroxynonenal (4-HNE). These processes occur not only in dopaminergic neurons but also in glial cells, amplifying oxidative stress and neuroinflammation. Our preliminary data show that the clinically safe fatty acid nitroalkene 10-nitro-oleic acid (10-NO₂-OA), presently in Phase 2 trials for treating obesity and inflammatory-related airway disease (NCT03762395) and soon (Q1 2026) in a clinical de-risking platform for PD (SLEIPNIR), crosses the blood brain barrier to attenuate nigrostriatal degeneration and motor deficits in chronic rotenone and AAV2-α-synuclein rat models of PD. Mechanistically, 10-NO₂-OA directly inhibits LRRK2 activity through covalent modification of nucleophilic cysteines while simultaneously inducing Nrf2-dependent aldehyde dehydrogenase-1A1 (ALDH1A1) to detoxify 4-HNE, thereby preventing oxidative stress-induced LRRK2 hyperactivation. Notably, ALDH1A1 knockdown abolishes 10-NO₂-OA-mediated neuroprotection in primary midbrain neurons, validating this dual mechanism. Our central hypothesis is that 10-NO2-OA represents a disease-modifying therapy for PD that confers neuroprotection by simultaneously inhibiting LRRK2 hyperactivation and preventing oxidative stress via increased ALDH1A1 expression and enhanced 4-HNE detoxification. This hypothesis will be tested through two Specific Aims: Aim 1 will define cell type–specific mechanisms of 10-NO₂-OA neuroprotection in primary ventral midbrain cultures and in chronic rotenone models of PD, focusing on ALDH1A1-dependent suppression of LRRK2 kinase activity and oxidative stress. Aim 2 will establish mechanistic robustness and translational relevance of 10-NO₂-OA in a chronic AAV2-mediated human α-synuclein rat model of PD. Completion of this research plan will define 10-NO₂-OA cell-specific neuroprotective mechanisms via inhibition of LRRK2 activity and ALDH1A1 upregulation, establish efficacy across chronic toxin- and α-synuclein–based models of PD, and a clinically relevant delayed-onset rotenone model of PD. Overall, these studies will advance 10-NO₂-OA as a safe dual-target therapeutic strategy with disease-modifying potential for Parkinson’s disease, improving the quality of life in patients and alleviating the already unbearable economic burden of PD.