Alpha-synuclein Fibrils Inhibit Activation of the BDNF/ERK Signaling Loop in the mPFC to Induce Parkinson's Disease-like Alterations with Depression.
10.1007/s12264-024-01323-x
- Author:
Zhuoran MA
1
;
Yan XU
1
;
Piaopiao LIAN
1
;
Yi WU
1
;
Ke LIU
1
;
Zhaoyuan ZHANG
1
;
Zhicheng TANG
1
;
Xiaoman YANG
2
,
3
;
Xuebing CAO
3
,
4
Author Information
1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
2. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430000, China. dryoung94@
3. com.
4. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China. caoxuebing@
- Publication Type:Journal Article
- Keywords:
BDNF;
CREB;
ERK;
Parkinson’s disease with depression;
SEW2871;
mTOR;
pS129
- MeSH:
Animals;
Brain-Derived Neurotrophic Factor/metabolism*;
alpha-Synuclein/metabolism*;
Male;
Prefrontal Cortex/drug effects*;
Rats, Sprague-Dawley;
Depression/metabolism*;
MAP Kinase Signaling System/drug effects*;
Rats;
Parkinson Disease/metabolism*;
Receptor, trkB/metabolism*;
Phosphorylation;
Disease Models, Animal;
Signal Transduction
- From:
Neuroscience Bulletin
2025;41(6):951-969
- CountryChina
- Language:English
-
Abstract:
Depression (Dep) is one of the most common concomitant symptoms of Parkinson's disease (PD), but there is a lack of detailed pathologic evidence for the occurrence of PD-Dep. Currently, the management of symptoms from both conditions using conventional pharmacological interventions remains a formidable task. In this study, we found impaired activation of extracellular signal-related kinase (ERK), reduced levels of transcription and translation, and decreased expression of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) of PD-Dep rats. We demonstrated that the abnormal phosphorylation of α-synuclein (pS129) induced tropomyosin-related kinase receptor type B (TrkB) retention at the neuronal cell membrane, leading to BDNF/TrkB signaling dysfunction. We chose SEW2871 as an ameliorator to upregulate ERK phosphorylation. The results showed that PD-Dep rats exhibited improvement in behavioral manifestations of PD and depression. In addition, a reduction in pS129 was accompanied by a restoration of the function of the BDNF/ERK signaling loop in the mPFC of PD-Dep rats.
