Huntington disease alters the actionable information in plasma extracellular vesicles

HD is primarily a neurodegenerative, mixed movement disorder, however, non-neuronal tissues such as liver and skeletal muscle also display various pathological changes.1 In line with this, we have recently shown that molecular signatures of inflammation, energy metabolism and vesicle biology are different in peripheral tissues of HTT mutation carriers (MTM-HD study).2 EVs are secreted by most, if not all cells. Since all EVs are generated with material from the secreting cell, analysis of their composition potentially allows insights into the molecular state of these cells, including in the context of disease.3 Following the updated guidelines of the International Society for Extracellular Vesicles (MISEV2018),4 we established a robust, fast and highly standardised threefold purification procedure for EVs of all types from human plasma (Figure 1A). Transmission electron microscopy of purified, negatively stained EVs showed the expected cup shaped morphology (Figure S2). Gene ontology analysis using Enrichr5 showed a high expression of many dysregulated proteins in liver indicating that liver might be the main source of the observed changes in EV protein content and composition. The liver therefore might be in a biologically more advanced HD state similar to neuronal populations.10 Taken together, our RNA data indicate that peripheral EVs are indeed an attractive source of easily accessible biomarkers since HTT sequences and/or potentially HTT-derived small RNAs are associated with EVs. [...]the classifier we developed can distinguish HTT mutation carriers at a molecular level with very high sensitivity in the prodromal stages of HD before the onset of diagnostic motor signs, that is, in the population most likely to participate in future clinical trials aiming at disease modification.