Around 55 million individuals worldwide are affected by dementia, a group of neurodegenerative disease that include memory loss and cognitive deficits. Even though dementia is common, there aren’t many good treatments for it. This is partly because researchers still don’t know the exact genetic and cellular causes of dementia.
Researchers from Harvard Medical School and Harvard T. H. Chan School of Public Health are leading a team that has made progress in understanding the process underlying a kind of dementia that first manifests in childhood.
According to a study published on October 7 in Nature Communications, the buildup of certain lipids in the brain that is linked to a genetic form of frontotemporal dementia (FTD) is caused by a lack of proteins that messes up the metabolism of cells.
The findings, which are based on studies in both animal models and human brain cells, offer fresh perspectives on FTD that may guide the development of novel treatments. The researchers added that the results reveal a metabolic disruption pathway that might be important in different types of dementia.
A Black Box
Dementia comes in a variety of forms, each having a complex genetic makeup involving several mutations. FTD, which is characterized by a loss of brain cells in the frontal and temporal lobes, causes 5 to 10% of dementia cases. The hereditary variants frequently manifest in patients between the ages of 45 and 65, and they frequently cluster in families. A specific mutation in the GRN gene, which prevents brain cells from producing a protein called progranulin, is about 15% of the time associated with FTD.
Progranulin has been associated with lysosomes, cellular organelles in charge of clearing out waste and other metabolic processes. But according to co-senior author Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology in the Department of Cell Biology in the Blavatnik Institute at HMS, “the function of the protein, especially its position in the lysosome, has remained something of a black box.”
In addition to lead authors Sebastian Boland, a former research fellow in the Farese & Walther Lab, and Sharan Swarup, a former research fellow in the Harper lab, Harper worked on the study with co-senior authors Tobias Walther and Robert Farese Jr., who were professors of cell biology at Harvard Medical School and professors of molecular metabolism at Harvard Chan School, respectively, when they conducted the research.
First, the researchers found that gangliosides, which are lipids that are common in the nervous system, built up in progranulin-deficient human cell lines, mouse brains, and brain cells from FTD patients.
The scientists then examined the kinds and concentrations of proteins and lipids found inside lysosomes using recently discovered technologies for lysosome purification. Using this method, the researchers discovered that lysosomes in these cells and tissues from brains with FTD had lower-than-normal levels of a lipid called BMP, which is necessary to break down gangliosides, the lipids commonly found in the central nervous system, as well as reduced levels of progranulin. But when BMP was added to cells, researchers noticed that these cells collected much less ganglioside.
The results suggest that progranulin in lysosomes helps keep the BMP levels high enough to stop brain cells from making gangliosides, which may contribute to FTD.
Farese added, “We have shown a role for progranulin in allowing normal degradation of gangliosides.” This showed that the problem might be fixable.
“Our findings are compatible with approaches that may be therapeutically advantageous,” said Walther. “People are already working on treatments that entail providing patients a source of progranulin,” he said. He also said that by changing BMP instead of progranulin, it might be possible to make treatments that target a different part of the system.
The researchers think that a similar lysosome-based mechanism could help with neurodegenerative disease other than FTD. This idea is quickly gaining support in the scientific community.
According to Harper, “the lysosome may be a major component of many distinct types of neurodegenerative disorders, but these diseases likely all interface with the lysosome in various ways.” For instance, researchers already know that lysosomal activity is regulated by a protein linked to a hereditary form of Parkinson’s disease. Farese said that more research needs to be done to fully understand how different lipids and proteins interact with lysosomes in neurodegenerative diseases.
The researchers are currently looking for linkages between a number of genes related to lysosomal function, including genes connected to lysosomal storage disorders. The mechanism by which progranulin raises BMP levels in the brain remains a key open question. Additional research is required to better understand the phases of the system the researchers discovered and to explain how lipid accumulation leads to cognitive deterioration.
This study shows the value of cooperation and adherence to scientific principles, according to Walther. The author said that “you can occasionally unearth things that are unexpected by utilizing the correct tools and asking the right detailed questions
