Life Science Research Institute, Kindai University, Osaka-Sayama, Osaka, 589-8511, Japan.
Department of Neurology, Kindai University, Faculty of Medicine, Osaka-Sayama, Osaka, 589-8511, Japan.
Neurochem Int. 2022 Jul;157:105357. doi: 10.1016/j.neuint.2022.105357. Epub 2022 May 4.
Polyglutamine (PolyQ) diseases are a group of inherited neurodegenerative diseases including Huntington's disease and several types of spinocerebellar ataxias, which are caused by aggregation and accumulation of the disease-causative proteins with an abnormally expanded PolyQ stretch. Extracellular vesicles (EVs) are membrane particles that are released from cells, including exosomes, microvesicles, and other extracellular particles. Recent studies have suggested that the PolyQ proteins, which are the disease-causative proteins of PolyQ diseases, and its aggregates are secreted via EVs, similar to the aggregation-prone proteins associated with other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The PolyQ proteins that are secreted from cells can transmit intercellularly, which may contribute to pathological propagation of the PolyQ protein aggregates in patient brain, and therefore, the pathological roles of EVs in the onset and progression of PolyQ diseases has attracted much attention. EVs may also mediate intercellular transfer of heat shock proteins and other neuroprotective factors, which are beneficial for protein homeostasis and cell survival, and thus, have therapeutic potential for the neurodegenerative diseases including PolyQ diseases. Furthermore, because EVs contain not only the disease-associated proteins, but also various proteins, miRNAs and other components, and changes in the levels of these contents might reflect pathological changes, EVs derived from blood, cerebrospinal fluid, and urine would be a potential source of minimally invasive diagnostic biomarkers that report disease-associated changes in PolyQ diseases. In this review, we summarize the current understanding of the pathological roles of EVs in PolyQ diseases, and therapeutic and diagnostic potential of EVs for these diseases. Elucidation of the pathological and physiological roles of EVs would lead to identification of a proper therapeutic target that would not interfere the protective roles of EVs for cell survival but suppress pathological propagation of the disease-causative proteins in PolyQ disease.
多聚谷氨酰胺（PolyQ）疾病是一组遗传性神经退行性疾病，包括亨廷顿病和几种脊髓小脑共济失调，这些疾病是由异常扩展的 PolyQ 延伸引起的致病蛋白聚集和积累引起的。细胞外囊泡（EVs）是从细胞中释放的膜颗粒，包括外泌体、微泡和其他细胞外颗粒。最近的研究表明，PolyQ 疾病的致病蛋白 PolyQ 蛋白及其聚集体通过 EVs 分泌，类似于与其他神经退行性疾病（如阿尔茨海默病和帕金森病）相关的易于聚集的蛋白。从细胞中分泌的 PolyQ 蛋白可以在细胞间传递，这可能有助于 PolyQ 蛋白聚集体在患者大脑中的病理性传播，因此，EVs 在 PolyQ 疾病的发病和进展中的病理作用引起了广泛关注。EVs 还可能介导热休克蛋白和其他神经保护因子的细胞间转移，这些因子有利于蛋白质内稳态和细胞存活，因此对包括 PolyQ 疾病在内的神经退行性疾病具有治疗潜力。此外，由于 EVs 不仅包含与疾病相关的蛋白，还包含各种蛋白、miRNA 和其他成分，并且这些内容物水平的变化可能反映出病理变化，因此来自血液、脑脊液和尿液的 EVs 将成为报告 PolyQ 疾病中与疾病相关变化的微创诊断生物标志物的潜在来源。在这篇综述中，我们总结了目前对 EVs 在 PolyQ 疾病中的病理作用的理解，以及 EVs 在这些疾病中的治疗和诊断潜力。阐明 EVs 的病理和生理作用将导致确定适当的治疗靶点，该靶点不会干扰 EVs 对细胞存活的保护作用，而是抑制 PolyQ 疾病中致病蛋白的病理性传播。
