Uncovering the role of c-Fos in the bidirectional relationship between depression/anxiety behaviors and α-synuclein propagation in Parkinson’s disease

Parkinson's disease (PD) presents with both motor and non-motor symptoms, including depression and anxiety, which often precede motor onset, yet the mechanisms linking these affective symptoms to PD pathology remain unclear. In this study, we investigated the bidirectional relationship between depression/anxiety behaviors and α-synuclein (α-syn) propagation using A53T α-syn transgenic mice subjected to chronic restraint stress (CRS) and/or intrastriatal injection of α-syn preformed fibrils (PFFs). Behavioral testing and immunohistochemical analyses revealed that CRS enhanced PFF-induced α-syn propagation and exacerbated depression/anxiety-like behaviors, while α-syn propagation was associated with aggravated CRS-induced behavioral deficits, indicating a potential reciprocal association that could contribute to accelerating PD progression. This interaction was mediated by the neuronal activity marker c-Fos. Pharmacological inhibition of c-Fos with T5224 mitigated both behavioral and pathological changes, and mGluR5 activation was found to partially contribute to c-Fos induction and α-syn spread. Together, these findings highlight a feedback interaction between affective symptoms and α-syn pathology in PD, mediated in part by neuronal activity-dependent mechanisms involving c-Fos and mGluR5, and suggest that early interventions targeting both neuronal activity and α-syn propagation may slow PD progression and improve patient quality of life.