Department of Biotechnologies and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy.
Milan Center of Neuroscience (NeuroMI), 20126 Milan, Italy.
Int J Mol Sci. 2021 Jan 19;22(2):943. doi: 10.3390/ijms22020943.
Amyloid aggregation of human ataxin-3 (ATX3) is responsible for spinocerebellar ataxia type 3, which belongs to the class of polyglutamine neurodegenerative disorders. It is widely accepted that the formation of toxic oligomeric species is primarily involved in the onset of the disease. For this reason, to understand the mechanisms underlying toxicity, we expressed both a physiological (ATX3-Q24) and a pathological ATX3 variant (ATX3-Q55) in a simplified cellular model, . It has been observed that ATX3-Q55 expression induces a higher reduction of the cell growth compared to ATX3-Q24, due to the bacteriostatic effect of the toxic oligomeric species. Furthermore, the Fourier transform infrared microspectroscopy investigation, supported by multivariate analysis, made it possible to monitor protein aggregation and the induced cell perturbations in intact cells. In particular, it has been found that the toxic oligomeric species associated with the expression of ATX3-Q55 are responsible for the main spectral changes, ascribable mainly to the cell envelope modifications. A structural alteration of the membrane detected through electron microscopy analysis in the strain expressing the pathological form supports the spectroscopic results.
人抗霉素-3（ATX3）的淀粉样聚集负责脊髓小脑性共济失调 3 型，属于多谷氨酰胺神经退行性疾病类别。人们普遍认为，有毒寡聚体的形成主要涉及疾病的发作。出于这个原因，为了了解毒性的机制，我们在简化的细胞模型中表达了生理（ATX3-Q24）和病理 ATX3 变体（ATX3-Q55）。已经观察到 ATX3-Q55 的表达导致细胞生长的降低高于 ATX3-Q24，这是由于有毒寡聚体的抑菌作用。此外，傅里叶变换红外微光谱研究，通过多元分析支持，使得能够在完整细胞中监测蛋白聚集和诱导的细胞扰动。特别是，已经发现与 ATX3-Q55 的表达相关的毒性寡聚体是主要光谱变化的原因，主要归因于细胞膜的修饰。通过在表达病理形式的菌株中进行的电子显微镜分析检测到的膜的结构改变支持了光谱结果。
