Fixing cellular recycling centers may help treat neurodegenerative diseases microbiologystudy

For neurodegenerative diseases such as Alzheimer’s and Parkinson’s, treatment options are scant. New research by Stanford scientists illuminates a promising target for treatment—increasing a lipid that boosts the trash-sorting functions of cells.

In a study published in Nature, the authors blocked an enzyme that degrades this lipid, which vastly improved a severe neurodegenerative disease in cells and in mice—a finding with potentially widespread applications in medicine.

“With neurodegenerative diseases, so far, we have no cure,” said study senior author Monther Abu-Remaileh, an assistant professor of chemical engineering and of genetics and Sarafan ChEM-H Institute Scholar. “We found an access point to therapeutics.”

Looking at lysosomes

Dysfunction in the lysosome, an organelle inside cells, has been implicated in neurodegenerative diseases. So the Stanford team has been studying the organelle for clues to treating neurodegenerative conditions.

The organelle disassembles larger molecules into smaller ones and redistributes nutrients throughout the cell.

“Lysosomes are basically the trash can of the cell,” explained Jian Xiong, a co-lead author of the study and a postdoctoral scholar in the Abu-Remaileh lab.

But when the gears get jammed in these waste-sorting facilities, junk molecules build up and grow toxic, which can ultimately kill cells.

This is especially a problem in the brain. Our neurons don’t divide like other cells—once we reach adulthood, neurons lost are not coming back.

“That’s why it’s important for the neurons to clear the trash efficiently,” said Xiong, who is also a member of Stanford’s Maternal & Child Health Research Institute and a postdoctoral fellow at the Knight Initiative for Brain Resilience.

One form of “trash” that can cause problems is excess cholesterol. A healthy lysosome handles cholesterol and transports it to other parts of the cell. But when this transporting function is dulled—as is often the case in neurodegenerative disease—cholesterol molecules build up so much that they lead to inflammation and death of cells.

In prior work, the team studied Batten disease, a rare but severe genetic neurodegenerative disease that’s characterized by lysosomal dysfunction. They identified a key lipid inside the lysosome that decreased in the disease, reducing the ability of the organelle to degrade and transport waste—excess fats—including its ability to transport cholesterol to other parts of the cell. The lipid is called bis(monoacylglycero)phosphate, or BMP.

“Basically, BMP greases the machinery,” said Abu-Remaileh, “allowing the lysosome to function at its best.”

For decades, scientists had believed that BMP is very stable in the lysosome. After finding initial evidence that BMP can be degraded in the lysosome, however, the team began sleuthing for molecular culprits for BMP’s breakdown.

They wondered, “What enzyme is degrading BMP?” said biochemistry Ph.D. student Kwamina Nyame, the study’s co-lead author and Mark and Mary Stevens Interdisciplinary Graduate Fellow with Stanford’s Wu Tsai Neurosciences Institute.

Boosting BMP

In the new study, the team discovered precisely how BMP is degraded in the lysosome.

By running experiments in test tubes, they found one enzyme is especially capable of breaking apart the lipid: a molecule known as PLA2G15.

With that critical enzyme revealed, the researchers went on to test whether removing or blocking it could treat degenerative brain disorders where disrupted lipid processing is at play. They focused on Niemann-Pick Disease type C, or NPC1—a genetic disorder sometimes referred to as “childhood Alzheimer’s” that impacts cells’ ability to distribute cholesterol through the lysosome, resulting in severe neurodegeneration in young children.

In different types of cells, including some from patients with NPC1, they modified genomes so that the cells no longer produced PLA2G15. The cells without PLA2G15 showed a promising response: BMP increased and the accumulation of cholesterol in the lysosome was cleared.

“This is literally the holy grail of this disease,” said Abu-Remaileh. “It means you have a therapeutic handle that you can then test in animal models.”

They then moved to a similar test in mice. They collaborated with researchers at the Netherlands-based biotech company Scenic Biotech, who had independently identified PLA2G15 as a target for treating cholesterol buildup. Mice genetically modified to develop NPC1 disease rarely live longer than 70 days.

But when the researchers further modified NPC1 mice to prevent them from producing the PLA2G15 enzyme, the animals lived nearly 65% longer. The rodents also had a sharp reduction in the death of neurons and improved measures of neuroinflammation and motor function.

“Seeing that you can actually improve the lifespan was huge,” said Nyame, who is also a Kolluri Graduate Fellow in the Chemistry/Biology Interface Training Program at Sarafan ChEM-H.

“This is the best result so far for this severe disease,” added Xiong. “This also encouraged us that it could be a general therapeutic strategy to treat neurodegenerative disease.”

Developing new therapies

Lysosomal cholesterol accumulation and other lipid recycling problems also appear in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and frontotemporal dementia. This similarity means that boosting BMP, and thus increasing cholesterol transport, could be a promising therapeutic strategy to help slow the progression of these more widespread disorders.

The team is now testing whether blocking the PLA2G15 enzyme improves outcomes in other neurodegenerative diseases in cells and animals. They are also screening hundreds of thousands of molecules to identify inhibitors of the PLA2G15 enzyme, the first step toward developing a drug that matches the beneficial effects of genetically blocking the enzyme.

At the same time, the researchers are also testing other enzymes that speed up BMP production—another strategy to increase the critical lipid, conducted as part of a partnership between the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute and the Innovative Medicines Accelerator.

The researchers are excited to uncover new treatment options for diseases that for so long have lacked them.

“We don’t really have novel drug targets in neurodegeneration,” said Abu-Remaileh. “These are bringing new hope.”