Abnormal molecular signatures of inflammation, energy metabolism, and vesicle biology in human Huntington disease peripheral tissues

Abstract

Background A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. Results We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients—those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. Conclusions Our ‘omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.

Smart Nanoscale Extracellular Vesicles in the Brain: Unveiling their Biology, Diagnostic Potential, and Therapeutic Applications

“…Moreover, the miHTT was also found in the CSF of the animal post-treatment, further confirming that EVs are indeed the source of miHTT-AAV propagation in the HD brain. 125 In a patient-based clinical trial, transcriptomics and proteomicsbased screening of peripheral EVs isolated from HD patients displayed a dysregulated EV profile, further suggesting that other than a predictor of pathogenic state, EVs can also be utilized as a biomarker for HD 126 (Table 1).…”

Huntington disease alters the actionable information in plasma extracellular vesicles

“…Philipp Nitzschner 1 Ronja Wagner 1 Julia Hummel 1 Franziska Hoschek 1 Maximilian Wagner 1 Alshaimaa Abdelmoez 1,2 Björn von Einem 1 G. Bernhard Landwehrmeyer 1 Sarah J. Tabrizi 3 Michael Orth 1,4,5…”

“…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. They are composed of lipids, proteins, RNAs and other small molecules and are generally categorised into three subtypes: exosomes, ectosomes and apoptotic bodies.…”

“…6 Further analysis of the clusters pointed towards regulation of these genes by REST, a transcriptional repressor involved in expression of cell identity genes and epigenetics, 7 which we also had identified by transcriptomic changes in adipose tissue from HTT mutation carriers. 2 We hypothesised that the RNA content of EVs could be used as an HD stage biomarker. To test this hypothesis, we used the expression data from the filtered datasets to generate unsupervised, rank-based Kendall clustering of the sample relationships (Figures 3A and S6).…”

“… 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 …”