title: Alpha-synuclein interferes with cAMP/PKA-dependent upregulation of dopamine β-hydroxylase and is associated with abnormal adaptive responses to immobilization stress.
abstract: 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.
authors.affiliation: College of Pharmacy, CHA University, Seongnam, Gyeonggi-do, South Korea; College of Pharmacy, Chonnam National University, Gwangju, South Korea.
authors.forename: Sasuk
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, College of Life Science, CHA University, Seoul, South Korea.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Park
authors.affiliation: Department of Bioengineering, College of Life Science, CHA University, Seoul, South Korea. Electronic address: jmoon@cha.ac.kr.
authors.forename: Jisook
authors.initials: J
authors.lastname: Moon
authors.affiliation: College of Pharmacy, CHA University, Seongnam, Gyeonggi-do, South Korea. Electronic address: hjchoi3@cha.ac.kr.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003623:Dark Adaptation / Q000502:physiology*; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000502:physiology*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D005576:Colforsin; D000242:Cyclic AMP; D004299:Dopamine beta-Hydroxylase; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Anxiety; CRE; ChIP; Chromatin immunoprecipitation; DBH; Dopamine β-hydroxylase (DBH); ECL; HPLC-ECD; High-performance liquid chromatography-electrochemical detector; IMO; LC; NE; NErgic; PBS; PD; Parkinson's disease; Stress; TH; alpha-synuclein; cAMP; cAMP response element; cyclic AMP; dopamine β-hydroxylase; enhanced chemiluminescence; immobilization stress; locus coeruleus; norepinephrine; norepinephrinergic; phosphate-buffered saline; tyrosine hydroxylase; α-SYN; α-Synuclein