NUS researchers link neurodegenerative disease protein to defective cholesterol metabolism
Published: 05 Aug 2021
Researchers from the NUS Yong Loo Lin School of Medicine have discovered that restoring cholesterol levels through drug intervention could be a novel therapeutic approach for diseases associated with TDP-43. The TDP-43 protein is linked to multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
From these findings, it is possible that drugs which modulate cholesterol metabolism might be a novel therapeutic strategy to treat these multiple neurodegenerative diseases. This is especially so if cholesterol dysmetabolism is proven to directly cause neurodegeneration.
Assistant Professor Ling Shuo-Chien from NUS Medicine’s Department of Physiology and his colleagues have previously shown that oligodendrocytes need TDP-43 to survive and wrap neurons in myelin. In this new study, it was found that a reason oligodendrocytes are dysfunctional in the absence of TDP-43 is that they are unable to synthesize or take up the cholesterol they need to sustain myelin production.
Cholesterol is a major component of myelin, with 25 per cent of the body’s total cholesterol being found in the central nervous system. Oligodendrocytes are known to synthesise large amounts of cholesterol for themselves, but they can also acquire it from other brain cells called astrocytes. The research team determined that, in the absence of TDP-43, oligodendrocytes lack many of the enzymes required to synthesise cholesterol. They also have reduced levels of the low density lipoprotein receptor that can take in cholesterol from outside the cell. Supplementing these TDP-43-deficient cells with cholesterol restored their ability to maintain the myelin sheath.
“Our results indicate that simultaneous disruption of cholesterol synthesis and uptake is likely one of the causes of the demyelination phenotype observed in models with TDP-43-deficient oligodendrocytes, and suggest that defects in cholesterol metabolism may contribute to ALS and FTD, as well as other neurodegenerative diseases characterised by TDP-43 aggregates,” said Asst Prof Ling.
Learn more in the article here and press release here.
