α-Synuclein-Related Mitochondria-Nrf2 Dysfunction in Parkinson's Disease Olfactory Mucosa.

Abstract

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. ONs obtained by nasal brush from 41 well-phenotyped patients with PD (n = 24 PD de novo [PD^dn] and n = 17 under treatment [PD^tr]) 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. 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 PD^dn ONs, Nrf2 mostly presented in the inactive cytosolic localization with a major reduction of SOD-1 expression, whereas in PD^tr, 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. 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;98:699-710.