Yeni araştırma, belirli bir genetik mutasyonun neden olduğu frontotemporal demansın temel biyolojisi hakkında fikir veriyor.
- Yeni bulgular, belirli bir genetik mutasyonun neden olduğu yıkıcı bir nörodejeneratif hastalık olan frontotemporal demansın temel biyolojisine ışık tutuyor.
- Araştırmacılar, genetik bir frontotemporal demans formunun, bozulmuş hücre metabolizmasının neden olduğu beyinde anormal lipid birikimi ile bağlantılı olduğunu ortaya çıkardı.
- Araştırma, frontotemporal bunamaya yol açan sürecin temel bir bileşenini ortaya koyuyor ve sonuçlar, hedeflenen tedavilerin geliştirilmesine yardımcı olabilir.
Dünya çapında yaklaşık 55 milyon kişi, hafıza kaybına ve bilişsel bozukluklara neden olan bir grup nörodejeneratif durum olan demanstan etkilenmektedir. Bununla birlikte, yaygın olarak görülmesine rağmen, kısmen araştırmacıların demansın kesin moleküler ve hücresel nedenlerinden hala emin olmamasından dolayı çok az etkili tedavi vardır.
Harvard Tıp Okulu ve Harvard TH Chan Halk Sağlığı Okulu’ndan araştırmacılar, yaşamın erken dönemlerinde ortaya çıkan bir bunama türünün ardındaki mekanizmayı anlamada ilerleme kaydeden bir ekibe liderlik ediyor.
Araştırmacılar, frontotemporal demansın (FTD) genetik bir formunun beyinde belirli lipitlerin birikmesiyle bağlantılı olduğunu ve bu birikimin hücre metabolizmasını bozan bir protein eksikliğinden kaynaklandığını bulmuşlardır. Bulgular yakın zamanda dergide yayınlandı
Previous studies have linked progranulin to parts of the cell called lysosomes, which are responsible for cleanup and other metabolic activities in cells. However, “the function of the protein, including its role in the lysosome, has remained sort of a black box,” said 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.
Harper collaborated on the study with co-senior 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 lead authors Sebastian Boland, a former research fellow in the Farese & Walther Lab, and Sharan Swarup, a former research fellow in the Harper lab.
The researchers initially found that progranulin-deficient human cell lines and mouse brains, as well as brain cells from patients with FTD, had an accumulation of gangliosides — lipids commonly found throughout the nervous system.
Next, the team used recently developed technology for purifying lysosomes to analyze the types and amounts of proteins and lipids present inside them. Using this technique, the scientists found that lysosomes in these cells and tissues from brains with FTD had reduced levels of progranulin, as well as lower-than-normal levels of a lipid called BMP, which is required to break down gangliosides, the lipids commonly found in the central nervous system. However, when researchers added BMP to cells, they observed that these cells accumulated far lower levels of gangliosides.
Together, the findings suggest that progranulin in lysosomes helps maintain the BMP levels needed to prevent gangliosides from accumulating in brain cells — buildup that may contribute to FTD.
“We’ve uncovered a role for progranulin in supporting proper degradation of gangliosides,” while also 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 results are consistent with that approach potentially being therapeutically beneficial,” Walther added. Moreover, it may be possible to develop therapies that focus on replacing BMP rather than progranulin, he said, and thus target a different part of the mechanism.
The researchers also think that a similar lysosome-based mechanism could be relevant for neurodegenerative diseases beyond FTD — an idea that they note is rapidly gaining ground in the field.
“The lysosome may be a key feature of many kinds of neurodegenerative diseases — but these diseases likely all connect with 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 aspects of lysosomal function. More research is needed, Farese added, to understand precisely how various lipids and proteins interact with lysosomes within the context of different neurodegenerative diseases.
Now, the researchers are studying several genes linked with lysosomal function, including genes associated with lysosomal storage diseases, to find connections between them. A central remaining question is how progranulin elevates BMP levels in the brain. Additional studies are needed to further elucidate the steps of the mechanism the team uncovered and to explain how lipid accumulation translates into cognitive decline.
“This study demonstrates the power of collaboration and following the science,” Walther said. “By using the right tools and asking the right detailed questions, you can sometimes uncover things that are unexpected.”
Reference: “Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis” by Sebastian Boland, Sharan Swarup, Yohannes A. Ambaw, Pedro C. Malia, Ruth C. Richards, Alexander W. Fischer, Shubham Singh, Geetika Aggarwal, Salvatore Spina, Alissa L. Nana, Lea T. Grinberg, William W. Seeley, Michal A. Surma, Christian Klose, Joao A. Paulo, Andrew D. Nguyen, J. Wade Harper, Tobias C. Walther and Robert V. Farese Jr., 7 October 2022, Nature Communications.
The study was funded by the Bluefield Project to Cure FTD, the National Institutes of Health, Google Ventures, Third Rock Ventures, the Aligning Science Across Parkinson’s initiative, the Canadian Institutes of Health Research, and the Howard Hughes Medical Institute.
Disclosures: Wade Harper is a founder and scientific advisory board member of Caraway Therapeutics Inc. and a founding scientific board member of Interline Therapeutics Inc. Robert Farese Jr. serves gratis on the board of the Bluefield Project to Cure FTD. Tobias Walther is a founder and scientific advisory board chair of Antora Bio Inc.