Alpha-synuclein interferes with cAMP/PKA-dependent upregulation of dopamine β-hydroxylase and is associated with abnormal adaptive responses to immobilization 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 alpha-synuclein (alpha-SYN) interferes with cAMP/PKA-dependent transcriptional activation in norepinephrine (NE)-producing cells, the effect of wild-type and mutant alpha-SYN on cAMP response element (CRE)-mediated regulation of the NE-synthesizing enzyme dopamine beta-hydroxylase (DBH) was evaluated in this study. Overexpression of wild-type or mutant alpha-SYN interfered with CRE-mediated regulation of DBH transcription in NE-producing SK-N-BE(2) cells. Upon entering the nucleus, alpha-SYN interacted with the DBH promoter region encompassing the CRE, which interfered with forskolin-induced CREB binding to the CRE region. Interestingly, mutant A53T alpha-SYN showed much higher tendency to nuclear translocation and interaction with the DBH promoter region encompassing the CRE than wild type. In addition, A53T alpha-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 alpha-SYN in NErgic neuronal cells, which further indicates that the alpha-SYN mutation may play a causative role in the generation of non-motor symptoms in PD. (C) 2013 Elsevier Inc. All rights reserved.