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 language | American English |
|---|---|
| Article number | 73 |
| Journal | Genome Biology |
| Volume | 22 |
| Issue number | 1 |
| DOIs | |
| State | Published - 4 Mar 2021 |
Bibliographical note
Funding Information:Alzheimer-related data were provided by the Rush Alzheimer?s Disease Center, Rush University Medical Center, Chicago. The review history is available as Additional?file?6. Barbara Cheifet was the primary editor of this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Funding Information:
This work was supported by The Israel Science Foundation [1140/17] to E.M.; National Institute of Health [R01NS100529 and NS094422] to L.M.E.; Support was also provided by “The Taube Family Program in Regenerative Medicine Genome Editing for Huntington's Disease” to LME. New York University and New York Genome Center startup funds (to N.E.S.), National Institute of Health /National Human Genome Research Institute [R00HG008171, DP2HG010099], National Institute of Health /National Cancer Institute [R01CA218668], Defense Advanced Research Project Agency [D18AP00053], the Sidney Kimmel Foundation, and the Brain and Behavior Foundation (to J.Z.L.); National Institute of Health [1R01-HG009761, 1R01-MH110049, 1DP1-HL141201]; the Howard Hughes Medical Institute; the New York Stem Cell, Simons, and G. Harold and Leila Mathers Foundations; the Poitras Center for Psychiatric Disorders Research at MIT; the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, J. and P. Poitras, and the Phillips Family to F.Z.; F.Z. is a New York Stem Cell Foundation–Robertson Investigator. E.M. is the Arthur Gutterman Family Chair for Stem Cell Research. M.S. is supported by an Azrieli PhD Fellowship, Azrieli Foundation.
Funding Information:
The Mathys et al. [] AD data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. The work was supported in part by grants P30AG10161, R01AG15819, R01AG17917, and U01AG61356.
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