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Cholesterol Metabolism Defects Linked to ALS

Medically reviewed by Susan Kerrigan, MD and Marianne Madsen on February 4, 2023

A 2021 study published in the Journal of Cell Biology has linked a defect in cholesterol metabolism to the development of neurological damage caused by amyotrophic lateral sclerosis (ALS).


How cholesterol relates to ALS


ALS causes damage to the myelin sheath, a substance that coats neurons and enables them to efficiently transmit electrical signals throughout the body. When this sheath is damaged, the neurons cannot function as intended, resulting in a range of physical and psychological symptoms. The myelin sheath relies on cholesterol to produce its coating, to such an extent that the central nervous system contains 25% of the body’s cholesterol, most of which is stored in the myelin.


Now, researchers are theorizing that a deficiency of a protein called TDP-43 could be responsible for the development of ALS, as this protein is critical for the production and maintenance of myelin. A lack of TDP-43 could impair the myelin’s ability to properly utilize cholesterol.


The study


Researchers at the Yong Loo Lin School of Medicine of the National University of Singapore conducted experiments in mice to determine how myelin-producing cells, called oligodendrocytes, are affected by a lack of TDP-43.


“We found that mice with oligodendrocytes lacking TDP-43 develop progressive neurological phenotypes leading to early lethality. These phenotypes were accompanied by the death of oligodendrocytes and progressive loss of myelin,” said Shuo-Chien Ling, a co-author of the study. In essence, a lack of TDP-43 led to a defect in the oligodendrocytes’ ability to synthesize cholesterol and produce myelin as intended. 


The researchers also used cell models to observe how TDP-43-deficient oligodendrocytes responded when given cholesterol. They found that the extra cholesterol restored their ability to produce myelin.


What this means for patients


Although human subjects weren’t used in the study, the researchers say a similar defect might impair TDP-43 function in patients with neurodegenerative diseases like ALS. Ling and his team analyzed the brain matter of deceased frontotemporal dementia (FTD) patients and found changes in their oligodendrocytes’ gene expression. In particular, their oligodendrocytes “produced lower amounts of two key enzymes required for cholesterol synthesis.” 


“Defects in cholesterol metabolism may contribute to ALS and FTD, as well as other neurodegenerative diseases characterized by TDP-43 aggregates,” said Ling. The team’s research could one day be used to help create new cholesterol metabolism-modulating drugs.


Written by Natan Rosenfeld

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