TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination
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Cholesterol metabolism is disturbed in the brains of mice and people with certain neurodegenerative diseases — a finding that could lead to new therapies.
The protein TDP43 has been implicated in several neurodegeneration disorders including amyotrophic lateral sclerosis and frontotemporal dementia.
Now, a team led by researchers at the National University of Singapore has found that in mouse models TDP43 interacts with a master regulator of cholesterol metabolism.
This perturbs the biosynthesis and uptake of this brain-fuelling fat inside critical support cells of the central nervous system. As a result, cholesterol levels drop, the protective coating around neurons thins out, and brain cells die off.
Post-mortem tissue analysis from people who died of frontotemporal dementia also showed TDP-43–mediated changes in the activity of key genes associated with cholesterol.
Cholesterol supplements helped protect the mice’s brains; similar treatments could be beneficial in humans as well.
- Journal of Cell Biology 220, e201910213 (2021). doi: 10.1083/jcb.201910213