Cholesterol-Dependent Changes in Fragile X Astrocytes
Maija Castren, MD, PhD
University of Helsinki
Iryna Ethell, PhD
University of California at Riverside
2019-2020 Grant Funding: $45,000
FRAXA awarded $45,000 to Dr. Maija Castrén, a Senior Researcher at the University of Helsinki, Finland, to study the role of astrocytes in Fragile X syndrome. Astrocytes are the most abundant glial cells and are non-neurons in the brain that perform many of the “household” chores. With this award, Dr. Castren collaborated with Dr. Iryna Ethell at the University of California at Riverside to investigate mechanisms underlying beneficial effects of lovastatin and cholesterol-dependent changes seen in the Fragile X brain.
A number of Fragile X studies have shown that astrocytes and other glial cells play important roles in Fragile X syndrome (FXS). Indeed, removing FMRP from astrocytes alone causes much of the pathology seen in the Fragile X brain. In a completely different line of research, scientists have shown that absence of FMRP causes abnormal metabolism of lipids (fatty acids), which the brain uses to send signals from cell to cell.
This project is aimed at the intersection of these two lines of investigation. Dr. Castrén is using human patient-specific induced pluripotent stem cells (iPSC) to examine how altered lipid metabolism in astrocytes affects the brain in FXS. She is focusing on the contribution of cholesterol-mediated mechanisms. Dysregulated cholesterol production is implicated in FXS and there is evidence that lovastatin, which lowers cholesterol, has beneficial effects in FXS. The data will be validated in astrocyte-specific Fmr1 knockout mice.
This research will improve understanding of cholesterol-dependent mechanisms in the brain. Studies of patient-specific cells will pave a way for development of human cell-based screening assays and biomarker discovery in FXS.