Genome Biology (Sep 2022)

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

  • Andreas Neueder,
  • Kerstin Kojer,
  • Tanja Hering,
  • Daniel J. Lavery,
  • Jian Chen,
  • Nathalie Birth,
  • Jaqueline Hallitsch,
  • Sonja Trautmann,
  • Jennifer Parker,
  • Michael Flower,
  • Huma Sethi,
  • Salman Haider,
  • Jong-Min Lee,
  • Sarah J. Tabrizi,
  • Michael Orth

DOI
https://doi.org/10.1186/s13059-022-02752-5
Journal volume & issue
Vol. 23, no. 1
pp. 1 – 21

Abstract

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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.

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