Paper of the month

Meshorer's Lab: Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity

Sorek, M., Oweis, W., Nissim-Rafinia, M. et al.

Genome Biol 22, 73 (2021)  (2021)

Lay summary:

Neurodegenerative diseases, such as Alzheimer’s disease and Huntington’s disease, develop gradually

as cells in the brain begin to die. Previous studies have shown that diseased and healthy neurons differ in the expression levels of many genes. However, these results are typically based on the average of millions of cells, masking the details of the gene expression distribution among the different neurons. Here we measured gene expression in single cells. We found that the gene expression patterns of diseased neurons extracted from the brains of Alzheimer’s disease and Huntington’s disease patients (post-mortem) were more heterogeneous compared to neurons obtained from healthy controls, suggesting compromised regulation in the disease state. Next, in order to test whether this was only a characteristic of later stages of neurodegeneration, we used a genetic model of Huntington’s disease, with cells derived from patients that carry the disease-causing mutation. The patient cells were “reprogrammed” to pluripotent stem cells, the correlate of young embryonic state, and were then differentiated into young developing neurons. Surprisingly, many genes that had similar average expression levels in both healthy and diseased young neurons, were in fact more variable in the diseased state. This increased gene expression variability was also evident in young neurons that carried a mutation that causes autism, a neurodevelopmental disorder. These findings suggest that although neurodegenerative diseases develop over time, imbalance in gene expression regulation is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.

“Working memory”