Study of the Week: Understanding the Mechanism of Frontotemporal Dementia

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

We previously published about this research in a story titled “Frontotemporal Dementia: The Latest Discoveries” which can be found here. The study was originally published in the scientific journal Nature Communications. You can read the full text of the study here

This research team was led by scientists at Harvard Medical School.

What Happened?

Dementias encompass a range of disabling, neurodegenerative conditions that are believed to affect around 55 million people around the world. Unfortunately, treatments are limited for these conditions. This is partially because scientists have yet to understand how these diseases originate on a cellular and molecular level. In this study, a team of researchers sought to deepen their understanding of frontotemporal dementia (FTD) and found that a genetic form of the disease was linked to a buildup of certain lipids in the brain. Furthermore, they attributed this buildup to a protein deficiency that disrupts cell metabolism.

A genetic cause of this type of dementia is found in around 15 percent of cases and may be the result of a mutation in a gene called GRN. The mutation causes the brain to stop its production of a certain protein called progranulin. The function of this protein, however, isn’t well understood. However, it has been linked to the activity of the lysosome, a cell organelle responsible for processing waste. The team looked at mouse models and human cell lines that were progranulin-deficient. These were compared to the brain cells of frontotemporal dementia patients.

What they found were that all of these cells had accumulated gangliosides, which are lipids that can be found all over the nervous system. They also purified the cell lysosomes so that they could identify the proteins and lipids that they held. These lysosomes had abnormally low progranulin and lower levels of BMP, a type of lipid. This lipid plays a role in breaking down gangliosides.

If the scientists added extra BMP to the cells, the concentration of gangliosides went down. What the researchers determined was that progranulin in the lysosomes normally helps prevent the accumulation of gangliosides by maintaining levels of BMP. Meanwhile, the accumulation of gangliosides may play a role in the development of frontotemporal dementia. Furthermore, the study appears to have found a potential method for reversing this mechanism.

About Frontotemporal Dementia

Frontotemporal demetia, also called frontotemporal degeneration disease, is an early onset form of dementia distinguished by degeneration of the temporal and frontal lobes of the brain. It is less common than Alzheimer’s disease, comprising at most 20 percent of dementia cases. While the cause is not clear in all cases, frontotemporal dementia appears to have a genetic component, with mutations in genes such as MAPT, VCP, and GRN having been identified as causing the illness, just to name a few. Onset of symptoms is usually between 45 and 65 years. These symptoms can vary as there are several different subtypes of the diseases. However, they can include loss of emotional and behavioral control, changes to personality and temperament, screaming, vulgar speech, dissociation from family, and compulsive buying disorder. There is no cure, but SSRIs can help manage behavior symptoms. Patients typically survive from 2 to 20 years following diagnosis. To learn more about frontotemporal dementia, click here.

Why Does it Matter?

The results of this study represent real progress in the understanding of frontotemporal dementia caused by mutations of the GRN gene. The researchers were able to understand with much greater clarity the vital role of the progranulin protein in maintaining normal function of the brain.

“We’ve uncovered a role for progranulin in supporting proper degradation of gangliosides.” – Robert Farese, Jr., senior author

The next steps in research are already clear: find a way to administer a supplementation of the progranulin protein:

“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.” – Tobias Walther, senior author

Another potential approach would to be to develop a treatment that would replace lost BMP, which would act on a different part of the mechanism. A mechanism based on the activity of lysosomes is also gaining ground in other neurodegenerative illnesses as well. A protein identified in Parkinson’s disease has been implicated in lysosome function, for example.

Further study will be needed to understand how progranulin boosts the brain’s BMP levels and deepen the understanding of the mechanism found in this research.

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