Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity

Matan Sorek, Walaa Oweis, Malka Nissim-Rafinia, Moria Maman, Shahar Simon, Cynthia C. Hession, Xian Adiconis, Sean K. Simmons, Neville E. Sanjana, Xi Shi, Congyi Lu, Jen Q. Pan, Xiaohong Xu, Mahmoud A. Pouladi, Lisa M. Ellerby, Feng Zhang, Joshua Z. Levin, Eran Meshorer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Background: Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained. Results: Analyzing single-cell RNA sequencing from Alzheimer’s disease (AD) and Huntington’s disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/− cells, a model for autism spectrum disorder. Conclusions: Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.

Original languageAmerican English
Article number73
JournalGenome Biology
Volume22
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Huntington’s disease
  • Neurodegenerative diseases
  • Neurological diseases
  • Pluripotent stem cells
  • Single cell
  • Smart-seq2
  • Stem cell model
  • Transcriptional heterogeneity
  • scRNA-seq

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