A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation

<div><p>Autophagy dysfunction is implicated in the pathogenesis of Parkinson disease (PD). BECN1/Beclin 1 acts as a critical regulator of autophagy and other cellular processes; yet, little is known about the function and regulation of BECN1 in PD. In this study, we report that dopamine D2 and D3 receptor (DRD2 and DRD3) activation by pramipexole and quinpirole could enhance <i>BECN1</i> transcription and promote autophagy activation in several cell lines, including PC12, MES23.5 and differentiated SH-SY5Y cells, and also in tyrosine hydroxylase positive primary midbrain neurons. Moreover, we identified a novel FOS (FBJ murine osteosarcoma viral oncogene homolog) binding sequence (5′-TGCCTCA-3′) in the rat and human <i>Becn1</i>/<i>BECN1</i> promoter and uncovered an essential role of FOS binding in the enhancement of <i>Becn1</i> transcription in PC12 cells in response to the dopamine agonist(s). In addition, we demonstrated a critical role of intracellular Ca<sup>2+</sup> elevation, followed by the enhanced phosphorylation of CAMK4 (calcium/calmodulin-dependent protein kinase IV) and CREB (cAMP responsive element binding protein) in the increases of FOS expression and autophagy activity. More importantly, pramipexole treatment ameliorated the SNCA/α-synuclein accumulation in rotenone-treated PC12 cells that overexpress wild-type or A53T mutant SNCA by promoting autophagy flux. This effect was also demonstrated in the substantia nigra and the striatum of <i>SNCA</i><sup>A53T</sup> transgenic mice. The inhibition of SNCA accumulation by pramipexole was attenuated by cotreatment with the DRD2 and DRD3 antagonists and <i>Becn1</i> siRNAs. Thus, our findings suggest that DRD2 and DRD3 agonist(s) may induce autophagy activation via a BECN1-dependent pathway and have the potential to reduce SNCA accumulation in PD.</p></div>