NEURON-SPECIFIC METABOLIC DYSFUNCTION TRIGGERS SYSTEMIC REMODELING IN A PARKINSONIAN MOUSE MODEL

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder in which mitochondrial complex I (MCI) dysfunction plays a pivotal role. In a mouse model with selective loss of MCI activity in dopaminergic neurons (MCI-Park), we observed nigrostriatal degeneration, motor deficits, and dopamine depletion. Notably, expression of the alternative NADH dehydrogenase NDI1 in dopaminergic neurons (MCI-Park/NDI1) fully restored motor and non-motor behavior, neuronal survival, and striatal dopamine levels, highlighting the therapeutic potential of restoring mitochondrial NADH oxidation. Here, we investigated whether MCI deficiency induces systemic proteomic alterations detectable in plasma, and whether such alterations can be reversed by NDI1 expression. Using plasma from wild-type, MCI-Park, and MCI-Park/NDI1 mice, we performed high-throughput plasma proteomic profiling. Comparative proteomic analysis revealed clear differences among experimental groups. Many proteins were dysregulated in MCI-Park mice compared to wild-type, including proteins associated with metabolic reprogramming (e.g., CDH6), synaptic transmission (CLSTN2 or ADAM23), cell survival (S100A4, WISP1), and immune-related processes (VSIG, ACVRL1). Importantly, these changes were restored in MCI-Park/NDI1 mice, indicating that NDI1 expression can normalize protein alterations caused by MCI deficiency. Together, these findings demonstrate that restoration of mitochondrial NADH oxidation modulates systemic protein networks disrupted in parkinsonism, supporting MCI dysfunction as a multi-level therapeutic target for PD. Moreover, the identified plasma proteomic changes provide a valuable framework for future identification of circulating biomarkers. Although the analysis was performed in plasma from symptomatic mice, future work will extend this approach to prodromal mouse models and human cohorts to evaluate the translational potential of these proteomic signatures.