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Huntington Disease Gene Expression Signatures in Blood Compared to Brain of YAC128 Mice as Candidates for Monitoring of Pathology

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Abstract

While the genetic cause of Huntington disease (HD) is known since 1993, still no cure exists. Therapeutic development would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. Previously, HD-specific signatures were identified in human blood representing signatures in human brain, showing biomarker potential. Since drug candidates are generally first screened in rodent models, we aimed to identify HD signatures in blood and brain of YAC128 HD mice and compare these with previously identified human signatures. RNA sequencing was performed on blood withdrawn at two time points and four brain regions from YAC128 and control mice. Weighted gene co-expression network analysis was used to identify clusters of co-expressed genes (modules) associated with the HD genotype. These HD-associated modules were annotated via text-mining to determine the biological processes they represented. Subsequently, the processes from mouse blood were compared with mouse brain, showing substantial overlap, including protein modification, cell cycle, RNA splicing, nuclear transport, and vesicle-mediated transport. Moreover, the disease-associated processes shared between mouse blood and brain were highly comparable to those previously identified in human blood and brain. In addition, we identified HD blood-specific pathology, confirming previous findings for peripheral pathology in blood. Finally, we identified hub genes for HD-associated blood modules and proposed a strategy for gene selection for development of a disease progression monitoring panel.

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Availability of Data and Materials

The datasets generated and analyzed during the current study are available in the GEO repository, GSE170998.

Code Availability

The code used for the analyses is available at Zenodo: https://zenodo.org/record/5806116.

Abbreviations

CNS:

central nervous system

CSF:

cerebrospinal fluid

CPA:

concept profile analysis

DE:

differentially expressed

DGE:

differential gene expression

FDR:

false discovery rate

GO-BP:

Gene Ontology biological process

HD:

Huntington’s disease

HTT:

Huntingtin

logCPM:

log counts per million

logFC:

log fold change

mHTT:

mutant HTT

NfL:

neurofilament light

PCA:

principal component analysis

T1:

blood time point 1

T2:

blood time point 2

WGCNA:

weighted gene co-expression network analysis

WT:

wild-type

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Acknowledgements

The authors want to thank Melvin M. Evers for his help in the design of the animal studies.

Funding

This work was partly funded by Campagne Team Huntington. Sequencing was funded by the European Union seventh Framework Program (FP7/2007-2013), grant agreement no. 305,121 (Neuromics).

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Authors and Affiliations

  1. Department of Human Genetics, Leiden University Medical Center, 2333, ZC, Leiden, The Netherlands

    Elsa C. Kuijper, Lodewijk J. A. Toonen, Maurice Overzier, Kristina Hettne, Marco Roos, Willeke M. C. van Roon-Mom & Eleni Mina

  2. Department of Biomedical Data Sciences, Leiden University Medical Center, 2333, ZC, Leiden, The Netherlands

    Roula Tsonaka

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  1. Elsa C. Kuijper
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Contributions

Wet lab experiments were performed by M. O., E. C. K., and L. J. A. T. Analysis of RNA sequencing was done by E. C. K. and E. M. R. T. gave advice on statistical analysis. Experiments were designed by L. J. A. T., M. R., W. v. R. M., E. M., and K. H. Interpretation of data by E. C. K., M. R., W. v. R. M., and E. M. Writing of the paper was done by E. C. K. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Elsa C. Kuijper.

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All animal experiments were licensed by the Central Committee for Animal experiments (CCD) in AVD1160020171069, valid from 1 September 2017 until 1 September 2022.

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Kuijper, E.C., Toonen, L.J.A., Overzier, M. et al. Huntington Disease Gene Expression Signatures in Blood Compared to Brain of YAC128 Mice as Candidates for Monitoring of Pathology. Mol Neurobiol 59, 2532–2551 (2022). https://doi.org/10.1007/s12035-021-02680-8

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