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

Abstract Background Parkinson's disease (PD) is characterized by motor symptoms and significant non-motor symptoms, such as depression and anxiety, which often precede motor manifestations. This study investigates the bidirectional relationship between depression/anxiety behaviors and α-synuclein (α-syn) propagation in PD. Methods We used A53T α-syn transgenic mice, combining chronic restraint stress (CRS) and α-syn preformed fibrils (PFF) injection to explore the relationship. Behavioral assessments and immunohistochemical analyses were conducted to evaluate the effects of CRS and PFF on α-syn propagation and depression/anxiety-like behaviors. Additionally, c-Fos and mGluR5 were examined as potential mediators. Results Our findings reveal that depression/anxiety behaviors and α-syn propagation exacerbate each other, creating a vicious cycle that may accelerate PD progression. This interaction is mediated by the neuronal activity marker c-Fos. The c-Fos inhibitor T5224 ameliorated these effects, highlighting its potential as a therapeutic target. Additionally, mGluR5 activation partly contributes to this process. Conclusions The critical role of neuronal activity in the interplay between non-motor symptoms and neuropathology in PD suggests that early intervention strategies targeting both aspects may slow disease progression and improve quality of life.