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<p>Transcriptional dysregulation is among the most prominent molecular alterations in Huntington’s disease (HD). It is not confined to the brain but also extends to peripheral tissues and cells, enabling minimally invasive screening strategies to identify transcriptional surrogates of the health status in HD mutation carriers. Nonetheless, transcriptomics approaches have failed to identify consistent candidates from peripheral blood, probably due to the low impact of the HD mutation in the transcriptional profiles of circulating cells, which can be masked by the high cellular complexity of this biofluid. In this study, we applied for the first time single-cell RNA-seq to peripheral blood mononuclear cells (PBMCs) to determine which cells accumulate the most prominent gene expression changes, and therefore, represent potential sources of reliable biomarkers. We observed common transcriptional alterations across different blood cell subtypes, which were partially validated in published bulk transcriptomics datasets. To relate these gene expression patterns with disease progression in the absence of a large cohort of patients, we examined selected candidates in a phenotypically characterized cohort of transgenic R6/1 mice. Among the tested genes, only the variations in the interferon related gene <i>Irf7</i> in blood were mildly correlated with motor coordination performance in mutant mice. Notably, striatal <i>Irf7</i> expression did not show such phenotypical correlation in the same individuals. Overall, transcriptional-based changes in peripheral blood can be linked to HD but they are mild and not apparently confined to particular cellular subpopulations. In conclusion, dissection of individual blood cells in combination with subsequent validation in mouse models emphasizes the challenges in obtaining clinically relevant biomarkers in HD.</p>

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Single-cell transcriptomics and mouse model phenotyping for biomarker screen of peripheral blood in Huntington’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Paula Martín-Climent,
  • Samanta Ortuño-Miquel,
  • Juan F. Gallego-Serna,
  • Silvia Martí-Martínez,
  • Luis M. Valor

摘要

Transcriptional dysregulation is among the most prominent molecular alterations in Huntington’s disease (HD). It is not confined to the brain but also extends to peripheral tissues and cells, enabling minimally invasive screening strategies to identify transcriptional surrogates of the health status in HD mutation carriers. Nonetheless, transcriptomics approaches have failed to identify consistent candidates from peripheral blood, probably due to the low impact of the HD mutation in the transcriptional profiles of circulating cells, which can be masked by the high cellular complexity of this biofluid. In this study, we applied for the first time single-cell RNA-seq to peripheral blood mononuclear cells (PBMCs) to determine which cells accumulate the most prominent gene expression changes, and therefore, represent potential sources of reliable biomarkers. We observed common transcriptional alterations across different blood cell subtypes, which were partially validated in published bulk transcriptomics datasets. To relate these gene expression patterns with disease progression in the absence of a large cohort of patients, we examined selected candidates in a phenotypically characterized cohort of transgenic R6/1 mice. Among the tested genes, only the variations in the interferon related gene Irf7 in blood were mildly correlated with motor coordination performance in mutant mice. Notably, striatal Irf7 expression did not show such phenotypical correlation in the same individuals. Overall, transcriptional-based changes in peripheral blood can be linked to HD but they are mild and not apparently confined to particular cellular subpopulations. In conclusion, dissection of individual blood cells in combination with subsequent validation in mouse models emphasizes the challenges in obtaining clinically relevant biomarkers in HD.