Journal Article

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

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

2022

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adipose tissue / Animal Genetics and Genomics / Bioinformatics / biomarkers / Biomedical and Life Sciences / Biopsy / Body fat / Cell lines / Clinical trials / data collection / Datasets / disease progression / Energy Metabolism / Evolutionary Biology / Extracellular vesicles / Fibroblasts / gene ontology / Gene polymorphism / Genes / Homeostasis / Human Genetics / Humans / Huntington Disease - genetics / Huntington's disease / Huntingtons disease / Inflammation / Inflammation - complications / Life Sciences / Microbial Genetics and Genomics / Molecular modelling / Musculoskeletal system / Mutation / Nervous system / Neurodegeneration / Neurodegenerative Diseases / Ontology / Pathogenesis / Patients / Plant Genetics and Genomics / protein content / Proteins / Proteomics / RNA / Single-nucleotide polymorphism / Skeletal muscle / Skin / SNP sequencing / Transcription factors / Transcriptomics