Alpha-synuclein interferes with cAMP/PKA-dependent upregulation of dopamine β-hydroxylase and is associated with abnormal adaptive responses to immobilization stress

• α-SYN interferes with forskolin-induced DBH up-regulation in SK-N-BE(2)C cells.
• α-SYN enters into the nucleus where it binds to the CRE region of DBH promoter.
• A53T α-SYN transgenic mice exhibit higher depression/anxiety-like behaviors than normal mice.
• A53T α-SYN transgenic mice exhibit abnormal adaptive responses following repeated stress.

Parkinson's disease (PD) is clinically characterized not only by motor symptoms but also by non-motor symptoms, such as anxiety and mood changes. Based on our previous study showing that overexpression of wild-type or mutant α-synuclein (α-SYN) interferes with cAMP/PKA-dependent transcriptional activation in norepinephrine (NE)-producing cells, the effect of wild-type and mutant α-SYN on cAMP response element (CRE)-mediated regulation of the NE-synthesizing enzyme dopamine β-hydroxylase (DBH) was evaluated in this study. Overexpression of wild-type or mutant α-SYN interfered with CRE-mediated regulation of DBH transcription in NE-producing SK-N-BE(2) cells. Upon entering the nucleus, α-SYN interacted with the DBH promoter region encompassing the CRE, which interfered with forskolin-induced CREB binding to the CRE region. Interestingly, mutant A53T α-SYN showed much higher tendency to nuclear translocation and interaction with the DBH promoter region encompassing the CRE than wild type. In addition, A53T α-SYN expressing transgenic mice exhibited increased anxiety-like behaviors under normal conditions and abnormal regulation of DBH expression in response to immobilization stress with abnormal adaptive responses. These data provide an insight into the physiological function of α-SYN in NErgic neuronal cells, which further indicates that the α-SYN mutation may play a causative role in the generation of non-motor symptoms in PD.