Emerging roles of extracellular vesicles in polyglutamine diseases: Mutant protein transmission, therapeutic potential, and diagnostics

Abstract

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.

Keywords: Biomarker; Exosome; Extracellular vesicle; Polyglutamine disease; Therapy; Transmission.