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古老的第二信使环磷酸腺苷(cAMP)与新型细胞死亡机制协同作用:对阿尔茨海默病和帕金森病潜在的转化治疗益处。

The old second messenger cAMP teams up with novel cell death mechanisms: potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease.

作者信息

Zhang Tong, Luu Minh D A, Dolga Amalia M, Eisel Ulrich L M, Schmidt Martina

机构信息

Department of Molecular Pharmacology, University of Groningen, Groningen, Netherlands.

Department of Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, Netherlands.

出版信息

Front Physiol. 2023 Jun 19;14:1207280. doi: 10.3389/fphys.2023.1207280. eCollection 2023.

Abstract

Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent neurodegenerative disorders severely impacting life expectancy and quality of life of millions of people worldwide. AD and PD exhibit both a very distinct pathophysiological disease pattern. Intriguingly, recent researches, however, implicate that overlapping mechanisms may underlie AD and PD. In AD and PD, novel cell death mechanisms, encompassing parthanatos, netosis, lysosome-dependent cell death, senescence and ferroptosis, apparently rely on the production of reactive oxygen species, and seem to be modulated by the well-known, "old" second messenger cAMP. Signaling of cAMP via PKA and Epac promotes parthanatos and induces lysosomal cell death, while signaling of cAMP via PKA inhibits netosis and cellular senescence. Additionally, PKA protects against ferroptosis, whereas Epac1 promotes ferroptosis. Here we review the most recent insights into the overlapping mechanisms between AD and PD, with a special focus on cAMP signaling and the pharmacology of cAMP signaling pathways.

摘要

阿尔茨海默病(AD)和帕金森病(PD)是最常见的神经退行性疾病,严重影响着全球数百万人的预期寿命和生活质量。AD和PD呈现出截然不同的病理生理疾病模式。然而,有趣的是,最近的研究表明,AD和PD可能存在重叠机制。在AD和PD中,包括PARP-1依赖性细胞死亡、NETosis、溶酶体依赖性细胞死亡、衰老和铁死亡在内的新型细胞死亡机制,显然依赖于活性氧的产生,并且似乎受到著名的“老”第二信使cAMP的调节。cAMP通过PKA和Epac发出的信号促进PARP-1依赖性细胞死亡并诱导溶酶体细胞死亡,而cAMP通过PKA发出的信号则抑制NETosis和细胞衰老。此外,PKA可防止铁死亡,而Epac1则促进铁死亡。在此,我们综述了AD和PD之间重叠机制的最新见解,特别关注cAMP信号传导以及cAMP信号通路的药理学。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a0d/10315612/41f59c8bf32d/fphys-14-1207280-g001.jpg

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