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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Parkinson's disease: acid-glucocerebrosidase activity and alpha-synuclein clearance
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Parkinson's disease: acid-glucocerebrosidase activity and alpha-synuclein clearance

机译：帕金森氏病：酸性葡萄糖脑苷脂酶活性和α-突触核蛋白清除率

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摘要

The role of mutations in the gene GBA1 encoding the lysosomal hydrolase -glucocerebrosidase for the development of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, was only very recently uncovered. The knowledge obtained from the study of carriers or patients suffering from Gaucher disease (a common lysosomal storage disorder because of GBA1 mutations) is of particular importance for understanding the role of the enzyme and its catabolic pathway in the development of synucleinopathies. Decreased activity of -glucocerebrosidase leads to lysosomal dysfunction and the accumulation of its substrate glucosylceramide and related lipid derivatives. Glucosylceramide is suggested to stabilize toxic oligomeric forms of -synuclein that negatively influence the activity of -glucocerebrosidase and to partially block export of newly synthesized -glucocerebrosidase from the endoplasmic reticulum to late endocyticcompartments, amplifying the pathological effects of -synuclein and ultimately resulting in neuronal cell death. This pathogenic molecular feedback loop and most likely other factors (such as impaired endoplasmic reticulum-associated degradation, activation of the unfolded protein response and dysregulation of calcium homeostasis induced by misfolded GC mutants) are involved in shifting the cellular homeostasis from monomeric -synuclein towards oligomeric neurotoxic and aggregated forms, which contribute to Parkinson's disease progression. From a therapeutic point of view, strategies aiming to increase either the expression, stability or delivery of the -glucocerebrosidase to lysosomes are likely to decrease the -synuclein burden and may be useful for an in depth evaluation at the organismal level.
机译：直到最近才发现突变在编码溶酶体水解酶-葡萄糖脑苷脂酶的基因GBA1中对突触核病（例如帕金森氏病和路易氏体痴呆）的发展的作用。从对携带者或患有高雪氏病（由于GBA1突变而导致的常见溶酶体贮积病）的患者的研究中获得的知识对于理解该酶及其分解代谢途径在突触核病发展中的作用特别重要。 -葡萄糖脑苷脂酶的活性降低导致溶酶体功能障碍及其底物葡萄糖基神经酰胺和相关脂质衍生物的积累。建议使用葡萄糖基神经酰胺来稳定毒性的-synuclein寡聚形式，从而对-glucocerebrosidase的活性产生负面影响，并部分阻止新合成的-glucocerebrosidase从内质网向晚期内吞室的输出，从而扩大-synuclein的病理作用并最终导致神经元细胞死亡。这种致病性的分子反馈回路和最可能的其他因素（例如，内折叠网突变相关的受损，未折叠的蛋白质反应的激活以及由错误折叠的GC突变体引起的钙稳态的失调）都参与了细胞稳态从单体突触核蛋白向寡聚体的转变。神经毒性和聚集形式，有助于帕金森氏病的进展。从治疗的观点来看，旨在增加β-葡萄糖脑苷脂酶向溶酶体的表达，稳定性或递送的策略可能会降低β-突触核蛋白的负担，并且可能在生物体水平的深度评估中有用。

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