Our recent transcriptome analysis of the brains of people with Down syndrome (DS),
conducted from fetal stages to 40 years old, identified approximately 800 dysregulated
genes across all chromosomes, each with specific temporal and regional profiles. These
altered genes form co-expression networks, the most prominent of which indicates
defective oligodendrocyte (OL) development and myelination. This finding is consistent
with imaging studies demonstrating reduced white matter integrity in individuals with DS.
In this collaborative study between the Haydar and Gallo labs, we will answer key
questions regarding the timing and source of OL dysmaturation, and particularly whether
cell-autonomous or non-cell autonomous mechanisms lead to altered cellular
differentiation and myelination. The Aims of the project progress from defining the
developmental time course of OL dysmaturation to comprehensive and integrated
transplantation, behavioral and functional tests to evaluate the mechanism(s) of the
defect. Whether these changes can be rescued by gene dosage normalization or by
using newly identified pharmacological tools to prompt OL maturation will be studied in
the last Aim.