Neuromelanin and Alpha-Synuclein in Parkinson's disease: Toward Neuroprotective Strategies

Parkinsons disease (PD) is a neurodegenerative disorder characterized by the progressive loss of neuromelanin (NM)-containing neurons in the substantia nigra pars compacta (SNpc). Aging is the most significant risk factor for the disease, while synuclein plays a crucial role in its progression, particularly through the formation of Lewy bodies (LBs). In this study, we employed a novel NM-based PD mouse model generated by overexpressing human tyrosinase (hTyr) in the SNpc using adeno-associated viral vectors (AAVs). This model was applied to different rodent strains that differ in their synuclein expression, allowing us to dissect the synergistic role of NM and synuclein in PD-related neurodegeneration. We further developed and characterized a humanized NM-SNCA mouse model (PAC-Tg(SNCA WT); Snca-/-), which mimics key pathological features of PD, including progressive nigrostriatal degeneration, synuclein aggregation, and neuroinflammation. Transcriptomic analysis of this model revealed significant alterations in biological pathways associated with human PD,identifying novel molecular targets for potential therapeutic intervention. Based on these findings, we evaluated two targeted treatments. First, we demonstrated that modulating neuroinflammation with Dexamethasone (DXM) significantly improved motor function and preserved dopaminergic neurons, likely through reduced microglial activation and decreased peripheral immune cell infiltration. Second, we focused on FKBP51, a co-chaperone involved in protein folding, whose expression increases significantly with aging and in PD-affected brains, suggesting it as a novel therapeutic target. In our study, pharmacological inhibition of FKBP51 using SAFit2 conferred neuroprotective effects reducing neuroinflammation and dopaminergic neurodegeneration, improving motor performance, and slowing the progression of the disease. These results suggest that FKBP51 inhibitors may represent a promising therapeutic strategy for PD, providing insights into novel mechanisms underlying the disease and offering potential interventions to slow its progression.