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

Abstract

Many neurodegenerative diseases (NDs) develop only later in life, when cells in the nervous system lose their structure or function. In genetic forms of NDs, this late onset phenomenon remains largely unexplained. Analyzing single cell RNA sequencing (scRNA-seq) from Alzheimer disease (AD) patients, we find increased transcriptional heterogeneity in AD excitatory neurons. We hypothesized that transcriptional heterogeneity precedes ND pathologies. To test this idea experimentally, we used juvenile forms (72Q; 180Q) of Huntington disease (HD) iPSCs, differentiated them into committed neuronal progenitors, and obtained 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 resulted in increased aggregate formation, a pathology associated with HD. We further validated the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder. Overall, our results suggest that although NDs 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.

Non-coding RNAs Associated with Prader-Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells

“…Thus, it may introduce errors in gene expression that accumulate during development and, as a consequence, manifest as PWS. Such a pathological pattern, where a transcriptional regulation imbalance emerges already in stem cells, impacts neuronal development and results in a late onset disease, has been reported for many neurodevelopmental disorders including Fragile X and Rett syndromes as well as neurodegenerative Alzheimer's and Huntington's diseases (Sabitha et al, 2021;Sorek et al, 2021). Mild but persistent effects on overall gene expression may be the reason why the deletions in the PWS locus are not lethal.…”