NRF2 Deletion Results in Mobility Impairment in A53TSyn Model of Synucleinopathy

Parkinson's Disease (PD) is the second most diagnosed neurological disorder globally, affecting millions of people worldwide. Oxidative stress is implicated in the progression of PD, yet its direct effects on motor function, particularly in the context of synucleinopathy, are not fully understood. Here, we investigated the effects of the loss of the antioxidant regulatory transcription factor NRF2 in the A53TSyn mouse model of synucleinopathy. Motor function was evaluated in separate cohorts of A53TSyn mice without NRF2 (A53TSyn/NRF2KO), as well as A53TSyn mice expressing NRF2 (A53TSyn/NRF2+) and healthy wild-type (WT) mice at four, six, and eight months of age. The overall mobility decreased in A53TSyn/NRF2KO mice relative to WT mice at all ages. Significant alterations in gait were also apparent in A53TSyn/NRF2KO mice compared to A53TSyn mice without NRF2 deletion. Expression of tyrosine hydroxylase (TH) was also quantified in the brains of those mice. While there were no differences in cortical pSyn expression between A53TSyn/NRF2+ and A53TSyn/NRF2KO mice, a reduction in TH abundance in the striatum was evident in A53TSyn/NRF2KO mice at all ages. In summary, our data suggest that NRF2 plays a role in maintaining mobility and gait in the context of synucleinopathy and may represent a therapeutic target to mitigate mobility decline in PD-affected individuals.