Fatty molecules help brain cells remove Huntington’s faulty protein
Study suggests boosting ganglioside levels may be useful therapeutic strategy
Complex fatty molecules called gangliosides are key to the formation of cellular shipping containers that help brain nerve cells get rid of improperly folded proteins, including the mutated huntingtin (mHTT) protein that drives Huntington’s disease, a study shows. These containers are known as extracellular vesicles (EVs).
“Now we know that when gangliosides are low — not just in Huntington’s disease but also in Parkinson’s and in other hereditary neurodegenerative diseases — the vesicle-mediated cell communication and clearance system doesn’t work properly,” Simonetta Sipione, PhD, the study’s senior author at the University of Alberta in Canada, said in a university news story. “This allows harmful proteins such as mutant huntingtin to accumulate and thus contributes to the processes that drive neurodegeneration.”
Gangliosides were found at low levels in cell models of Huntington’s, and the administration of gangliosides, particularly GM1, to these cells restored EV formation and promoted the release of mHTT within EVs.
The findings suggest that interventions to boost ganglioside levels may be a useful therapeutic strategy in Huntington’s and other neurodegenerative disorders.
“We are still working to understand the full picture of how gangliosides protect the brain and how they might be used as restorative therapies in neurodegenerative diseases,” said Sipione, who is already working with a biotech company to explore the possibility of testing this idea in clinical trials.
The study, “Gangliosides modulate the secretion of extracellular vesicles and their misfolded protein cargo,” was published in Science Advances.
Mutations in key gene result in mutant protein that drives Huntington’s
Huntington’s is caused by mutations in the HTT gene, which result in the production of a mutant huntingtin protein that forms toxic clumps in nerve cells. These toxic aggregates are thought to be a primary disease-driving mechanism.
Abnormal clumps of proteins in nerve cells are also hallmarks of other neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease.
In normal circumstances, nerve cells have a few ways to dispose of unneeded proteins. One way is to use EVs, tiny fat-based vesicles filled with molecular cargo that are released by cells. By packaging proteins into EVs and releasing these EVs outside the cell, cells can reduce the accumulation of unwanted proteins.
EVs can also act as messengers, transporting molecules between cells.
Gangliosides, which are part of the membranes that form EVs and are highly abundant in the brain and spinal cord, are composed of a type of complex fatty molecule attached to certain sugar molecules.
Previous studies by Sipione and colleagues have shown that the production of the ganglioside GM1 is decreased in Huntington’s and that GM1 treatment reduced brain levels of mHTT and motor symptoms in mouse models of the disease.
“However, whether altered ganglioside levels contribute to impaired EV secretion and how GM1 supplementation influences this process remains unknown,” the researchers wrote.
Increasing ganglioside levels helped facilitate EV generation
Through a series of experiments in lab-grown human and mouse cells, Sipione and colleagues demonstrated that when ganglioside levels are reduced, nerve cells are unable to produce EVs as effectively. Conversely, increasing ganglioside levels helped facilitate EV generation.
Lab-grown cells collected from people carrying a Huntington’s-causing mutation, which have been previously shown to have lower GM1 levels, released significantly fewer EVs than cells from age-matched healthy people.
Meanwhile, suppressing ganglioside production in Huntington’s cell models impaired the cells’ ability to remove mHTT in EVs, while GM1 administration increased the cells’ ability to excrete the abnormal protein in EVs.
“Together, our data suggest that through modulation of EV release, gangliosides can affect the disposal of pathogenic [disease-causing] proteins via EVs,” the researchers wrote.
Experiments in cellular models of Alzheimer’s and Parkinson’s, which involve the formation of toxic clumps of other proteins, yielded similar results.
Together, our data suggest that through modulation of EV release, gangliosides can affect the disposal of pathogenic [disease-causing] proteins via EVs.
Although these data suggest that boosting ganglioside levels could help nerve cells dispose of disease-causing proteins through EVs, this strategy has a potential drawback: the EVs themselves don’t just disappear; they are often taken up by other brain cells.
As such, increasing the amount of disease-causing protein in EVs could inadvertently help disease-causing proteins spread throughout the brain.
The scientists believe, however, that this is unlikely based on data from animal studies that suggested boosting ganglioside levels lowers overall brain levels of toxic proteins. Still, they cautioned a need for more studies to understand the underlying biology in greater detail.
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