Summary: Researchers have discovered how a fat protein, BMP, essential for brain perform, is produced, probably opening new doors for treating degenerative diseases like Alzheimer’s and frontotemporal dementia. Two proteins, PLD3 and PLD4, were found to accelerate the formation of BMP by changing the material’s “handedness”, allowing it to be secure in cells where another lipids are broken down.
This finding provides insight into how fat regulation in the brain works to reveal the accumulation of toxic substances in conditions like dementia. The study provides a promising new course for studying mental health and creating novel treatments.
Important Information:
- BMP, a fat essential for brain wellbeing, is produced by PLD3 and PLD4 proteins.
- These proteins change BMP’s “handedness”, allowing it to maintain in cells.
- Knowing BMP manufacturing could lead to treatments for Alzheimer’s and memory.
Origin: HHMI
Researchers have gained a better understanding of a protein that controls head lipid levels. This discovery may eventually lead to the development of treatments for conditions like Alzheimer’s and frontotemporal memory.
The results are  , published , in the journal , Cell.
How can a fatty molecule be created that is involved in the brain’s process of breaking down other fats but does n’t end up being destroyed itself? It’s a problem that has stifled researchers ‘ minds for the past 50 years.
BMP, or bis ( monoacylglycerol ) phosphate, is a phospholipid that is located in lysosomes—the cell’s garbage bins.
” BMP is a co-factor for decay, but itself is very, very secure, and it has an unexpected chemistry”, says Howard Hughes Medical Institute Investigator Tobias Walther. ” As a consequence, anyone knew how this is made”.
In the fresh research, Walther and Robert Farese, Jr.’s staff at the cell biology system of the Sloan Kettering Institute reports that two proteins, phospholipases D3 and D4 ( PLD3 and PLD4), are needed to make BMP in laboratory assays as well as in animal tissues and animal models.
For more than 15 years, Walther and Farese’s lab has investigated , frontotemporal dementia , (FTD), the disease that actor Bruce Willis was diagnosed with in 2023. It affects both the frontal and temporal lobes of the brain, which are responsible for personality, judgment, and speech.
FTD is the most prevalent cause of dementia in people under the age of 60, and there is no known cure or treatment for it.
In previous work, the researchers discovered that FTD patients had elevated levels of gangliosides, a type of lipid that is attached to a sugar, in their brains. It turned out that these molecules were accumulating due to a problem with their breakdown.
” That’s when we got really interested in this BMP molecule, and we found that it was extremely low in FTD brains”, says Farese.
High levels of gangliosides are toxic, and BMP activity levels are linked to neurodegenerative diseases, suggesting that controlling ganglioside levels is crucial for maintaining healthy brain function.
Mirror, mirror on the wall
As molecules go, BMP is peculiar, says Walther.
” Molecules have a pattern that is similar to a left or right hand, but one is a mirror image of the other,” he claims.
Although phospholipids and lipids are almost always” R”-type, BMP is one of the few phospholipids with the opposite” S” form. In fact, “handedness” can occur in two places in BMP, and both are in the S form.
The S handedness of BMP is what makes it so stable in the lysosome, when all of the other lipids—which are R—are destroyed. But the 50-year-old question is—if lipids are R, how does one of them become S?
According to Shubham Singh, a postdoctoral fellow at the Sloan Kettering Institute who conducted the study, changing a molecule’s handedness is a difficult task and only occasionally occurs.
” Everything in lipid biochemistry starts from one molecule called glycerol 3-phosphate, and it is R”, says Singh.
” So, at what step do you convert R to S, or right hand to left hand, to make BMP”?
Swap meet
Singh and colleagues observed that human cells swap, or exchange, a glycerol between two different molecules to make the S form of BMP in a reaction called transphosphatidylation.
Then, by poring through , protein sequences , for enzymes that look like they might interact with lipids, Singh decided to test phospholipase D enzymes.
Through a series of experiments, the researchers concluded that PLD3 and PLD4 catalyze the reaction. BMP levels were raised when PLD3 or PLD4 expression was altered, but levels dropped when PLD3 or PLD4 expression was altered.
Interestingly, PLD3 mutations that cause spinocerebellar ataxia 46, a rare neurodegenerative disease, or that increase Alzheimer’s risk also reduce BMP synthesis. When PLD3 was knocked out in mice, similar results on brain lipids were discovered.
” The paper’s findings that these two related enzymes, PLD3 and PLD4, produce BMP fills in a significant piece in the BMP puzzle, and these enzymes do so in an elegant way that results in inversion of the stereochemistry, or handedness, of parts of the molecule”, says Jeremy Baskin, a cell biologist at Cornell University, who was not involved in the work.
Because these two enzymes, in contrast to other members of the phospholipase D class, are not well understood, according to Baskin, who adds that the study expands the field’s understanding of PLD3 and PLD4.
In fact, he says that PLD3 and PLD4 were once thought to only break down nucleic acids, but now they appear to have a new role in making a lipid. Walstead claims that was the most unexpected outcome.
” We were also surprised by reports that another enzyme could produce BMP,” he says. BMP could be produced by that enzyme, but it was in the incorrect stereochemical form.
Now that the team knows more about a crucial step in BMP synthesis, they are looking at the lipid’s role in other , neurodegenerative diseases. And even though they have n’t yet taken any new treatments into account, it’s possible that these strategies will one day benefit patients.
In the end, Walther explains, the work is a demonstration of the value of basic research.
He claims that to go after this, it really took us to sit down and sketch out the paths with a little serendipity and perseverance.
There are still many of these fundamental discoveries and unturned stones to be made.
About this research in neurology and dementia
Author: Tobias Walther
Source: HHMI
Contact: Tobias Walther – HHMI
Image: The image is credited to Neuroscience News
Original Research: Open access.
“PLD3 and PLD4 synthesize S, S-BMP, a key phospholipid enabling lipid degradation in lysosomes” by Tobias Walther et al. Cell
Abstract
PLD3 and PLD4 synthesize S, S-BMP, a key phospholipid enabling lipid degradation in lysosomes
Bis ( monoacylglycero ) phosphate ( BMP ) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Neurodegenerative diseases are related to differences in BMP levels.
Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the , S , ( rather than the , R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial , S, S-stereochemistry is achieved is unknown.
Here, we report that phospholipases D3 and D4 ( PLD3 and PLD4 ) synthesize lysosomal , S, S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction , in , vitro.
When either enzyme is highly expressed ( brain for PLD3, spleen for PLD4), PLD3 or PLD4 significantly lower BMP levels in cells or murine tissues, leading to gangliosidosis and lysosomal abnormalities.
PLD3 mutants associated with neurodegenerative diseases, including risk of Alzheimer’s disease, diminished PLD3 catalytic activity.
We conclude that PLD3/4 enzymes synthesize lysosomal , S, S-BMP, a crucial lipid for maintaining brain health.
