神经炎症
葡萄糖脑苷酶
帕金森病
发病机制
小胶质细胞
共核细胞病
α-突触核蛋白
自噬
氧化应激
疾病
生物
神经科学
免疫学
医学
作者
Ru-Xue Bo,Yan-Yan Li,Tian-Tian Zhou,Nai-Hong Chen,Yu-He Yuan
标识
DOI:10.1016/j.neuropharm.2022.108964
摘要
The lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene, is a membrane-associated protein catalyzing the cleavage of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Homologous GBA1 mutations cause Gaucher disease (GD) and heterologous mutations cause Parkinson's disease (PD). Importantly, heterologous GBA1 mutations are recognized as the second risk factor of PD. The pathological features of PD are Lewy neurites (LNs) and Lewy bodies (LBs) composed of pathological α-synuclein. Oxidative stress, inflammatory response, autophagic impairment, and α-synuclein accumulation play critical roles in PD pathogenic cascades, but the pathogenesis of PD has not yet been fully elucidated. What's more, PD treatment drugs can only relieve symptoms to a certain extent, but cannot alleviate neurodegenerative progression. Therefore, it's urgent to explore new targets that can alleviate the neurodegenerative process. Deficient GCase can cause lysosomal dysfunction, obstructing the metabolism of α-synuclein. Meanwhile, GCase dysfunction causes accumulation of its substrates, leading to lipid metabolism disorders. Subsequently, astrocytes and microglia are activated, releasing amounts of pro-inflammatory mediators and causing extensive neuroinflammation. All these cascades can induce neuron damage and death, eventually promoting PD pathology. This review aims to summarize these points and the potential of GCase as an original target to provide some ideas for elucidating the pathogenesis of PD.
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