Linking TDP-43 Dysfunction, Cholesterol, and Maintenance of Myelin in Neurodegeneration
TDP-43 is one of the few proteins in the body that can misfold in ways that lead to solid aggregates that disrupt cell and tissue function. The biochemistry and relevance of TDP-43 is a more recent area of research in comparison to the study of, say, amyloid-β in Alzheimer's disease and α-synuclein in Parkinson's disease, but it appears important to the progression of a number of neurodegenerative conditions. Researchers here elaborate on the relationship between TDP-43 and age-related demyelination, the corrosion of myelin sheathing around axons that is necessary for nervous system function, normally maintained by a population of cells known as oligodendrocytes. Extreme demyelination leads to ultimately fatal conditions such as multiple sclerosis, but occurs to a lesser yet still harmful degree in normal aging, contributing to cognitive decline.
The TDP-43 protein is linked to multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 plays many vital roles within cells, but, under certain circumstances, it can clump together to form toxic aggregates that damage cells and prevent TDP-43 from performing its normal functions. TDP-43 aggregates are found in the brains of most ALS patients and ~45% of FTD patients and are also linked to several other neurodegenerative disorders, including some cases of Alzheimer's disease. The aggregates form not only in neurons, but also in other brain cell types such as oligodendrocytes. These latter cells protect neurons and speed up the transmission of nerve impulses by wrapping neurons in a fatty substance called myelin.
Researchers have previously shown that oligodendrocytes need TDP-43 to survive and wrap neurons in myelin. In the new study, researchers find that one 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 such a major component of myelin that 25% of the body's total cholesterol can be found in the central nervous system. Oligodendrocytes are known to synthesize large amounts of cholesterol for themselves, but they can also acquire it from other brain cells called astrocytes. Researchers determined that, in the absence of TDP-43, oligodendrocytes lack many of the enzymes required to synthesize cholesterol, and 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.
Similar defects in cholesterol metabolism may occur in patients, where the formation of aggregates might prevent TDP-43 from performing its normal functions. Researchers analyzed brain samples from FTD patients and found that their oligodendrocytes produced lower amounts of two key enzymes required for cholesterol synthesis, while the low density lipoprotein receptor was incorporated into TDP-43 aggregates.