Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson’s disease

Autor: Xiao-yun Niu, Xi-xiu Xie, Hou-zhen Tuo, Cui-ping Lv, Ya-ru Huang, Jie Zhu, Shi-yu Liang, Xiao-yu Du, Cheng-gang Yang, Sheng-jie Hou, Xiao-ying Sun, Ling-jie Li, Fang Cui, Qi-xin Huang, Ying-bo Jia, Yu-jiong Wang, Rui-tian Liu
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Cell Death Discovery, Vol 10, Iss 1, Pp 1-15 (2024)
Druh dokumentu: article
ISSN: 2058-7716
74621297
DOI: 10.1038/s41420-024-01939-y
Popis: Abstract The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson’s disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1β, which is subsequently secreted into the extracellular space. This secreted IL-1β then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.
Databáze: Directory of Open Access Journals
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