Park Jeongmin, Jin LiHua, Song Hyun-Chul, Chen Yingqing, Jang Eun Young, Park Gyu Hwan, Yang Chae Ha, Ryter Stefan W, Park Jeong Woo, Zheng Min, Joe Yeonsoo, Chung Hun Taeg
College of Korean Medicine, Daegu Haany University, Gyeongsan, Republic of Korea.
School of Nursing, YanBian University, Yanji, China.
Cell Death Discov. 2025 May 27;11(1):254. doi: 10.1038/s41420-025-02530-9.
Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are marked by progressive neuronal loss. Regulated cell death programs (i.e., necroptosis) as well as homeostatic mechanisms (i.e., autophagy) can modulate disease pathogenesis. Low-dose carbon monoxide (CO) has been shown to activate cytoprotective responses in various models of tissue injury. Our study investigates the protective roles of CO in neurodegenerative disease through the modulation of necroptosis and autophagy programs. We found that CO activates the Protein kinase RNA (PKR)-like ER kinase (PERK) branch of the unfolded protein response (UPR) and the calcineurin pathway, leading to significant neuroprotective effects in cellular and mouse models of PD. CO-induced PERK activation promotes the nuclear translocation of transcription factor EB (TFEB). Subsequently, TFEB enhances autophagy through increased expression of autophagy-related genes and inhibits necroptosis by suppressing the phosphorylation and oligomerization of Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL), a key necroptosis regulator. Furthermore, CO enhances the expression of Beclin 1, which inhibits necroptosis, independently of its autophagic function, by regulating MLKL oligomerization. Our findings suggest that modulation of the PERK-calcineurin pathway and downstream activation of cellular defense mechanisms by CO may serve as a promising therapeutic approach to mitigate neuronal loss in neurodegenerative diseases.
神经退行性疾病，如帕金森病（PD）和阿尔茨海默病（AD），其特征是神经元进行性丧失。受调控的细胞死亡程序（即坏死性凋亡）以及稳态机制（即自噬）可调节疾病的发病机制。低剂量一氧化碳（CO）已被证明能在各种组织损伤模型中激活细胞保护反应。我们的研究通过调节坏死性凋亡和自噬程序来研究CO在神经退行性疾病中的保护作用。我们发现，CO激活未折叠蛋白反应（UPR）的蛋白激酶RNA（PKR）样内质网激酶（PERK）分支和钙调神经磷酸酶途径，在PD的细胞和小鼠模型中产生显著的神经保护作用。CO诱导的PERK激活促进转录因子EB（TFEB）的核转位。随后，TFEB通过增加自噬相关基因的表达来增强自噬，并通过抑制关键坏死性凋亡调节因子混合谱系激酶结构域样假激酶（MLKL）的磷酸化和寡聚化来抑制坏死性凋亡。此外，CO增强Beclin 1的表达，Beclin 1通过调节MLKL寡聚化来抑制坏死性凋亡，而与其自噬功能无关。我们的研究结果表明，CO对PERK-钙调神经磷酸酶途径的调节以及细胞防御机制的下游激活可能是减轻神经退行性疾病中神经元丧失的一种有前景的治疗方法。
