α‐synuclein‐related mitochondria‐Nrf2 dysfunction in Parkinson's disease olfactory mucosa

Objective: The objective of this study was to outline the dynamics of the mitochondrial network and cytoprotective response in patients with Parkinson's disease (PD)-derived olfactory mucosa neurons (ONs) at different disease stages. Methods: ONs obtained by nasal brush from 41 well-phenotyped patients with PD (n = 24 PD de novo [PDdn] and n = 17 under treatment [PDtr]) and 29 healthy controls were examined through real-time polymerase chain reaction (RT-PCR), immunofluorescence, and Western blot. An integrative set of experiments using SH-SY5Y neuronal cells was also performed. Results: PD ONs accumulated α-synuclein oligomers in association with an aberrant subcellular distribution of mitochondrial markers COX IV and HSP60. DJ-1 ONs expression was permanently reduced in PD, revealing the mitochondrial dysfunction and justifying the defective Nrf2-mediated cytoprotective response. The Nrf2/SOD-1 pathway was indeed downregulated in PD ONs, although with stage-specific differences. In PDdn ONs, Nrf2 mostly presented in the inactive cytosolic localization with a major reduction of SOD-1 expression, whereas in PDtr, the Nrf2 active nuclear fraction increased, and the SOD-1 expression raised. In SH-SY5Y cells, we demonstrated that dopamine administration increases the Nrf2 nuclear fraction, acting as a possible pathway's inducer. Interpretation: Human-derived ONs may recapitulate PD pathogenic milestones, exhibiting stage-specific interactions among α-synuclein oligomers, mitochondrial metabolism, and cytoprotective response. These findings highlighted mitochondrial dysfunction as a primary target for therapeutic interventions and a potential axis for the biological stratification of patients. Moreover, they supported the translational value of ONs, as a source of biomarkers or models, which is critical in the current changing paradigm of PD toward a biological-based approach. ANN NEUROL 2025.