Summary: The genetic form of frontotemporal dementia is associated with an abnormal accumulation of fat in the brain fueled by impaired cellular metabolism. The findings could pave the way for new targeted therapies for FTD.
Dementia includes a group of neurodegenerative conditions that lead to memory loss and cognitive impairment and affect approximately 55 million people worldwide. However, despite its prevalence, there are few effective treatments, in part because scientists still do not understand exactly how dementia arises at the cellular and molecular level.
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 behind a type of dementia that strikes early in life.
In a study published October 7 in Nature CommunicationsIn this study, researchers discovered that the genetic form of frontotemporal dementia (FTD) is linked to the accumulation of certain fats in the brain – and this accumulation 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 related to other forms of neurodegeneration, the 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’ve uncovered the role of progranolin in supporting the proper decomposition of MRSA,” Faris said, while showing that it may 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 relate to 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.”
Finance and Authoring
Additional authors include Johannes Ampau, Pedro Malla, Ruth Richards, Alexander Fisher, Shubham Singh and Joao Paulo of HMS and Harvard Chan School. Jitika Agrawal and Andrew Nguyen of St. Louis University School of Medicine; Salvatore Spina, Alyssa Nana, Leah Greenberg, and William Seeley of the University of California, San Francisco; Michel Surma and Christian Klose of Lipotype GmbH.
The study was supported by the Bluefield to Cure FTD Project, the National Institutes of Health (R01NS083524; R01GM132129), Google Ventures, Third Rock Ventures, the Aligning Science Across Parkinson Initiative (ASAP-000282), the Canadian Institutes of Health Research and Howard Hughes Medical Institute.
Disclosures: Wade Harper is the founder and member of the scientific advisory board for Caraway Therapeutics Inc. and a founding scientific board member of Interline Therapeutics Inc. Robert Faris Jr. is offering his services free of charge to the Bluefield to Cure FTD Project Board of Directors. Tobias Walther is the founder and chair of the science advisory board for Antora Bio Inc.
About this FTD and genetics research news
author: Ekaterina Besheva
Contact: Ekaterina Besheva – Harvard
picture: The image is in the public domain
original search: open access.
“GRN gene deficiency leads to streptococcal diseaseWritten by Wade Harper et al. Nature Communications
GRN gene deficiency leads to streptococcal disease
Haploinsufficiency from GRN It causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is broken down into lysosomal granulin polypeptides. The function of lysosomes and why their absence leads to neurodegeneration is unclear.
Here we discover that human cells and brains of PGRN-deficient mice, as well as human frontal lobes of GRNFTD mutation Patients with increased levels of gangliosides, glycosphingolipids containing sialic acid.
In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of phosphate (BMP), a lipid needed for ganglioside catabolism, decreased with PGRN deficiency.
Our findings indicate that granules are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosideosis.
Accumulation of lysosomal glycosides may contribute to the neuroinflammation and neurodegenerative susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.