TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination

Cholesterol metabolism implicated in neurodegenerative diseases

28 February 2022

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.

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References

1. Journal of Cell Biology 220, e201910213 (2021). doi: 10.1083/jcb.201910213