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.

Public Health Relevance

The novel understanding of oligodendrocyte maturation defects in brains of humans with Down syndrome and the Ts65Dn mouse model open a new avenue to possible cognitive therapies for persons with Down syndrome?we have shown that these cellular defects lead to less myelin in the forebrain and cerebellum and that this causes slower neuronal transmission in the brain. The experiments in this proposal are designed to uncover the cell intrinsic and extrinsic mechanisms underlying the cellular defect and to measure whether motor and/or spatial learning and memory are correlated with the dysmyelination. Finally, we will investigate genetic and pharmacological therapies designed to promote myelination and improve cognitive and motor function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS105138-02
Application #
9663353
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118