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Exp Neurol. 2014 Feb;252:63-74. doi: 10.1016/j.expneurol.2013.11.009. Epub 2013 Nov 16.

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

Author information

1
College of Pharmacy, CHA University, Seongnam, Gyeonggi-do, South Korea; College of Pharmacy, Chonnam National University, Gwangju, South Korea.
2
Department of Bioengineering, College of Life Science, CHA University, Seoul, South Korea.
3
Department of Bioengineering, College of Life Science, CHA University, Seoul, South Korea. Electronic address: jmoon@cha.ac.kr.
4
College of Pharmacy, CHA University, Seongnam, Gyeonggi-do, South Korea. Electronic address: hjchoi3@cha.ac.kr.

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.

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

PMID:
24252179
DOI:
10.1016/j.expneurol.2013.11.009
[Indexed for MEDLINE]
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