New study sheds light on basic biology of the temporal front mental illness due to a specific genetic mutation.
Now, a team led by scientists at Harvard Medical School and Harvard T.H. Chan School of Public Health has made progress in revealing the mechanism Underlying a type of dementia that strikes early in life.
In a study published October 7 in Nature Communications, researchers discovered that the genetic form of frontotemporal dementia (FTD) is linked to the accumulation of certain fats in the brain — and this buildup results from a lack of a protein that interferes with cell metabolism.
The findings, based on experiments in human brain cells and animal models, provide new insights into FTD that could help design new treatments. Additionally, the findings highlight a mechanism of metabolic disturbance that may be relevant in other forms of neurodegenerationThe researchers said.
There are several different types of dementia, each with complex genes that involve different mutations. FTD, which is characterized by the loss of cells in the frontal and temporal lobes of the brain, accounts for 5 to 10 percent of cases of dementia. The genetic polymorphisms are most often diagnosed in patients between 45 and 65 years of age, and they tend to run in families. About 15 percent of the time, FTD is linked to a specific mutation in the GRN gene, which causes brain cells to stop making a protein called progranulin.
Previous studies have linked progranolin to parts of the cell called lysosomes, which are responsible for cleaning and other metabolic activities in cells. However, the protein’s function, including its role in the lysosome, has remained a kind of black box, said co-lead author Wade Harper, the Burt and Natalie Valley Professor of Molecular Pathology in the Department of Cell Biology at the Blavatnik Institute at HMS.
Harper collaborated on the study with co-lead authors Tobias Walther and Robert Faris Jr., who were professors of cell biology at HMS and professors of molecular metabolism at Harvard Chan School when they conducted the research, as well as lead authors Sebastian Poland, a former research fellow at Farese & Walther Lab, and Sharan Swarup, a former research fellow at Harper Lab.
The researchers first found that human cell lines and brains of progranulin-deficient mice, as well as brain cells from FTD patients, had an accumulation of gangliosides — lipids common throughout the nervous system.
Next, the team used a newly developed lysosome purification technique to analyze the types and amounts of proteins and lipids contained within them. Using this technique, the scientists found that lysosomes in these cells and tissues taken from FTD-affected brains lowered levels of progranulin, as well as lower-than-normal levels of a fatty substance called BMP, which is needed to break down gangliosides, a common fat. It is found in the central nervous system. However, when the researchers added BMP to the cells, they noticed that these cells accumulated much lower levels of Gangliosides.
Together, the results suggest that the progranulin found in lysosomes helps maintain the levels of BMP needed to prevent the accumulation of gangliosides in brain cells — an accumulation that may contribute to dystonia.
“We uncovered the role of progranolin in supporting proper decomposition of the germ,” Faris said, while also showing that it might be possible to correct the problem.
“People are already working on treatments that involve giving patients a source of progranolin, and our results are consistent with this potentially therapeutically beneficial approach,” Walther added. Furthermore, it may be possible to develop therapies that focus on replacing BMP rather than progranulin, he said, thus targeting a different part of the mechanism.
The researchers also believe that a similar lysosome-dependent mechanism could be relevant to neurodegenerative diseases beyond FTD – an idea they note is gaining rapid progress in the field.
“The lysosome may be a key feature of many types of neurodegenerative diseases — but it is possible that these diseases all associate with the lysosome in different ways,” Harper said. For example, scientists already know that a protein involved in the genetic form of Parkinson’s disease controls aspects of lysosomal function. Faris added that more research is needed to understand how different lipids and proteins interact with lysosomes in the context of various neurodegenerative diseases.
Now, researchers are studying several genes associated with lysosomal function, including those associated with lysosomal storage diseases, to find links between them. The central question remaining is how progranulin raises BMP levels in the brain. Additional studies are needed to further elucidate the steps of the mechanism discovered by the team and to explain how fat accumulation translates into cognitive decline.
“This study demonstrates the power of collaboration and science,” Walther said. “With the right tools and asking the right detailed questions, you can sometimes reveal unexpected things.”
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