Summary: A genetic form of frontotemporal dementia is associated with abnormal accumulation of lipids in the brain fueled by disrupted cellular metabolism. The findings could pave the way for new targeted therapies for FTD.
Dementia encompasses a range of neurodegenerative diseases that lead to memory loss and cognitive impairment and affect some 55 million people worldwide. Yet despite its prevalence, there are few effective treatments, in part because scientists still don’t understand exactly how dementia arises at the cellular and molecular level.
Now a team led by scientists from Harvard Medical School and Harvard TH Chan School of Public Health has made progress in unraveling the mechanism behind a type of dementia that strikes early in life.
In a study published on October 7 in Nature Communicationresearchers have found that a genetic form of frontotemporal dementia (FTD) is associated with the buildup of specific lipids in the brain – and this buildup results from a protein deficiency that interferes with cellular metabolism.
The results, based on experiments in human brain cells and animal models, provide new insights into FTD that could inform the design of new therapies. Additionally, the results highlight a mechanism of metabolic disruption that may be relevant in other forms of neurodegeneration, the researchers said.
A black box
There are several types of dementia, each with complicated genetics involving various mutations. FTD, characterized by loss of cells in the frontal and temporal lobes of the brain, accounts for 5-10% of dementia cases. Often diagnosed in patients between the ages of 45 and 65, the genetic forms tend to cluster in families.
About 15% of the time, FTD is linked to a specific mutation in the GRN gene, which prevents brain cells from making a protein called progranulin.
Previous studies have linked progranulin 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, remained something of a black box,” said co-lead author Wade Harper, Bert and Natalie Vallée 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 Farese 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 with lead authors Sebastian Boland, a former Farese & Walther Lab researcher, and Sharan Swarup, a former Harper Lab researcher.
The researchers first found that progranulin-deficient human cell lines and mouse brains, as well as brain cells from FTD patients, exhibited an accumulation of gangliosides – lipids commonly found throughout the nervous system.
Next, the team used newly developed technology to purify lysosomes to analyze the types and amounts of proteins and lipids present inside.
Using this technique, scientists found that the lysosomes of these FTD brain cells and tissues had reduced levels of progranulin, as well as lower than normal levels of a lipid called BMP, which is needed to break down proteins. gangliosides, lipids commonly found in the central nervous system.
However, when the researchers added BMP to the cells, they observed that these cells accumulated much lower levels of gangliosides.
Together, the results suggest that progranulin in lysosomes helps maintain BMP levels needed to prevent gangliosides from accumulating in brain cells – a buildup that may contribute to FTD.
“We discovered a role for progranulin in supporting proper ganglioside breakdown,” while showing that it may be possible to correct the problem, Farese said.
“People are already working on treatments that involve giving patients a source of progranulin, and our findings are consistent with this potentially therapeutically beneficial approach,” Walther added.
Additionally, it might be possible to develop therapies that focus on replacing BMPs rather than progranulin, he said, and thus target a different part of the mechanism.
The researchers also think a similar lysosome-based mechanism could be relevant to neurodegenerative diseases beyond FTD — an idea they say is rapidly gaining traction in the field.
“The lysosome may be a key feature of many types of neurodegenerative diseases – but these diseases are likely all related to the lysosome in different ways,” Harper said.
For example, scientists already know that a protein implicated in a genetic form of Parkinson’s disease controls certain aspects of lysosomal function. More research is needed, Farese added, to understand precisely how various lipids and proteins interact with lysosomes in the context of different neurodegenerative diseases.
Now, researchers are studying several genes related to lysosomal function, including genes associated with lysosomal storage diseases, to find links between them.
A central remaining question is how progranulin elevates BMP levels in the brain. Further studies are needed to further elucidate the steps of the mechanism discovered by the team and to explain how lipid accumulation translates to cognitive decline.
“This study demonstrates the power of collaboration and follow-up science,” Walther said. “By using the right tools and asking the right detailed questions, you can sometimes uncover unexpected things.”
Funding and authorship
Other authors included Yohannes Ambaw, Pedro Malia, Ruth Richards, Alexander Fischer, Shubham Singh and Joao Paulo of HMS and Harvard Chan School; Geetika Aggarwal and Andrew Nguyen of Saint Louis University School of Medicine; Salvatore Spina, Alissa Nana, Lea Grinberg and William Seeley from the University of California, San Francisco; Michal Surma and Christian Klose of Lipotype GmbH.
The study was supported by the Bluefield Project to Cure FTD, National Institutes of Health (R01NS083524; R01GM132129), Google Ventures, Third Rock Ventures, Aligning Science Across Parkinson’s Initiative (ASAP-000282), Institutes of Research in Health Canada and the Howard Hughes Medical Institute.
Disclosures: Wade Harper is Founder and Scientific Advisory Board Member of Caraway Therapeutics Inc. and Founding Scientific Advisory Board Member of Interline Therapeutics Inc. Robert Farese Jr. serves as a free member of the Bluefield Project to Cure FTD Board of Directors. Tobias Walther is Founder and Chairman of the Scientific Advisory Board of Antora Bio Inc.
About This FTD Research and Genetics News
Author: Ekaterina Pesheva
Contact: Ekaterina Pesheva – Harvard
Image: Image is in public domain
Original research: Free access.
“GRN frontotemporal dementia gene deficiency leads to gangliosidosis” by Wade Harper et al. Nature Communication
GRN frontotemporal dementia gene deficiency leads to gangliosidosis
Haploinsufficiency of NRG causes frontotemporal dementia (FTD). The NRG locus produces progranulin (PGRN), which is cleaved into lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear.
Here, we find that PGRN-deficient human cells and mouse brains, as well as human frontal lobes of NRG-patients with FTD by mutation have 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 bis(monoacylglycero)phosphates (BMPs), lipids required for ganglioside catabolism, were reduced with PGRN deficiency.
Our results indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis.
Accumulation of lysosomal gangliosides may contribute to neuroinflammation and susceptibility to neurodegeneration seen in FTD due to PGRN deficiency and other neurodegenerative diseases.