The central role of endoplasmic reticulum stress in Parkinson's disease and targeted therapeutic strategies.

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder. It is characterized by the progressive loss of dopaminergic neurons in the midbrain substantia nigra and the abnormal aggregation of α-synuclein. In recent years, ERS and the triggered UPR have been identified as a central role connecting multiple pathogenic factors in PD. This review systematically elaborates on the key pathological roles and molecular mechanisms of ERS in PD. In PD, various factors including genetic mutations, environmental toxins, and oxidative stress can disrupt ER homeostasis. These disruptions activate the UPR, which is mediated by the PERK, IRE1α, and ATF6 signaling pathways. A moderate UPR aims to restore cellular homeostasis. However, persistent or severe ERS can switch irreversibly to pro-apoptotic pathways, leading to neuronal death. More importantly, ERS interacts extensively with other PD-related pathological processes. It forms complex positive feedback loops with other core pathological processes in PD. These processes include the abnormal aggregation and propagation of α-synuclein, mitochondrial dysfunction, neuroinflammation, and impaired autophagic flux. Together, they drive the progressive neurodegeneration. Given its central role, targeting ERS has become a potential therapeutic strategy. This article focuses on discussing various intervention approaches, their research progress, and associated challenges. These include: UPR pathway-specific modulators; chemical chaperones; enhancers of protein degradation systems; existing drugs and natural products with ERS-modulating effects; neurotrophic factors and gene therapy; and traditional Chinese medicine. Finally, we discuss future research directions, including developing central nervous system-selective drugs, utilizing precision medicine for personalized treatment, and exploring combination therapies. The aim is to provide new perspectives for disease-modifying treatments of PD.