Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland.
Department Geriatrics and Social Work, Jesuit University Ignatianum in Cracow, Kopernika 26, 31-501 Cracow, Poland.
Int J Mol Sci. 2023 Jan 20;24(3):2044. doi: 10.3390/ijms24032044.
α-Synucleinopathies comprise a group of neurodegenerative diseases characterized by altered accumulation of a protein called α-synuclein inside neurons and glial cells. This aggregation leads to the formation of intraneuronal inclusions, Lewy bodies, that constitute the hallmark of α-synuclein pathology. The most prevalent α-synucleinopathies are Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). To date, only symptomatic treatment is available for these disorders, hence new approaches to their therapy are needed. It has been observed that mutations are one of the most impactful risk factors for developing α-synucleinopathies such as PD and DLB. Mutations in the gene, which encodes a lysosomal hydrolase β-glucocerebrosidase (GCase), cause a reduction in GCase activity and impaired α-synuclein metabolism. The most abundant gene mutations are N370S or N409S, L444P/L483P and E326K/E365K. The mechanisms by which GCase impacts α-synuclein aggregation are poorly understood and need to be further investigated. Here, we discuss some of the potential interactions between α-synuclein and GCase and show how mutations may impact the course of the most prevalent α-synucleinopathies.
α-突触核蛋白病包括一组以神经元和神经胶质细胞内一种称为α-突触核蛋白的蛋白质异常积累为特征的神经退行性疾病。这种聚集导致神经元内包涵体——路易体的形成，这构成了α-突触核蛋白病理学的标志。最常见的α-突触核蛋白病是帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩（MSA）。迄今为止，这些疾病只能进行对症治疗，因此需要新的治疗方法。已经观察到突变是导致α-突触核蛋白病（如 PD 和 DLB）的最具影响力的风险因素之一。编码溶酶体水解酶β-葡糖脑苷脂酶（GCase）的 基因的突变导致 GCase 活性降低和α-突触核蛋白代谢受损。最常见的 基因突变是 N370S 或 N409S、L444P/L483P 和 E326K/E365K。GCase 影响α-突触核蛋白聚集的机制尚未完全了解，需要进一步研究。在这里，我们讨论了α-突触核蛋白和 GCase 之间的一些潜在相互作用，并展示了 突变如何可能影响最常见的α-突触核蛋白病的病程。
