Nrf2/NOX2 Pathway Dysregulation and Oxidative Stress Biomarkers in Gaucher Disease-Associated Parkinsonism: Insights Into a Potential Therapeutic Target.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, yet its underlying genetic and molecular mechanisms remain incompletely understood. Variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase, are not only responsible for Gaucher disease (GD) but also represent a significant genetic risk factor for PD, contributing to lysosomal dysfunction, oxidative stress and autophagy impairment. Among the key regulators of redox homeostasis, the Nrf2/NOX2 signalling axis has emerged as a pivotal pathway in the modulation of neuroinflammation and neurodegeneration. This study aims to explore the pathogenic link between GBA mutations and PD, focusing on the redox imbalance and the role of Nrf2 signalling in an in vivo Gba D409V knock-in (KI) mouse model, compared to wild-type (WT) C57BL/6J controls. Animals 8-weeks old were evaluated over a 3-month period, with tissue and behavioural assessments conducted at 7, 14, 30, 60 and 90 days. Early timepoints (7 and 14 days) did not reveal significant changes in behavioural performance, expression of PD-related markers (TH, DAT, α-synuclein), or oxidative stress indicators, including Nrf2, NOX2, malondialdehyde (MDA) and nitrate/nitrite levels. However, at 30, 60 and especially 90 days, significant alterations emerged, particularly a disrupted Nrf2/NOX2 balance, accompanied by molecular and biochemical signatures of oxidative stress. These findings suggest a time-dependent progression of oxidative alterations in this GD model and support the role of GBA variants in promoting neurodegenerative processes. Unravelling these mechanisms is essential for the identification of early biomarkers and may offer new therapeutic insights for GBA1-associated PD.