School scientists identify faulty molecular recycling as potential driver of Alzheimer’s disease

Left to right: Matt Ravalin, Charles Craik, PhD, and Jason Gestwicki, PhD.

When a muscle or lung cell gets damaged beyond repair, self-destruct enzymes, known as caspases, spring into action, safely dismantling the cell. But in neurons, which are essentially irreplaceable, one of those enzymes actually helps to recycle old proteins instead of destroying the cell, a process that seems to stall during Alzheimer’s disease, recent findings in the UCSF School of Pharmacy show.

“When scientists think of caspases, they think of cell death,” said Charles Craik, PhD, faculty member in the School’s Department of Pharmaceutical Chemistry. “But it turns out that one of these caspases can actually regulate which proteins get destroyed in healthy cells, and which don't. And one of those proteins, tau, happens to build up during neurodegeneration.”

The research bolsters the idea that insufficient recycling of molecules inside the cell may underlie diseases like Alzheimer’s. Craik and Jason Gestwicki, PhD, also a faculty member in the Department of Pharmaceutical Chemistry, are co-senior authors on the study, which was published in Nature Chemical Biology on July 18.

The discovery happened when first author Matthew Ravalin, a graduate student who works in both the Craik Lab and the Gestwicki Lab, wanted to understand how certain proteins are marked for disposal in neurons. He developed an algorithm to hunt for proteins that could be chopped up by a particular caspase—caspase 6—and noticed that the resulting protein chunks always ended up with a specific molecular bar code on their ends.

Ravalin then scanned his lab’s database for other types of enzymes that help with the molecular recycling process, looking for those that might recognize this bar code. Ravalin reasoned that any enzyme that glommed onto that code might be picking up where caspase 6 had left off, ensuring that these protein fragments would be fully broken down.

His hunt led him to another enzyme, called a ubiquitin ligase—and “that’s when the light went on,” said Craik.

While caspases are akin to the “executioners” of the cell, according to Craik, ubiquitin ligases are more like the “sorters” in a large recycling facility. Healthy cells routinely must recycle old proteins and make new ones, and ubiquitin ligases put molecular tags on older proteins destining them for disposal.

Luckily, the School of Pharmacy is also home to an expert on these cellular sorters and the cellular recycling facility itself: Gestwicki.

“We were thrilled to see the interplay between caspase activity and ubiquitin ligases,” said Gestwicki. “These findings link two major cellular pathways in an unexpected way.”

Along with colleagues in the Craik and Gestwicki labs, Ravalin looked at the kinds of proteins that are recycled by the tag team of caspases and ubiquitin ligases. One of them was tau, a protein known to clump up in the brains of patients with neurodegeneration.

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Human neurons (red) grown in a petri dish, shown with toxic accumulation of tau protein (green), which can contribute to the development of Alzheimer's disease.

The finding suggested a connection to Alzheimer’s disease, where pieces of tau protein clump up in older people, damaging the brain.

The team then collaborated with UCSF’s Memory and Aging Center to analyze brain tissue from patients with Alzheimer’s disease and saw that these samples were largely missing the ubiquitin ligase needed to recycle tau. Sure enough, when these molecular sorters disappeared from the brain, bits of tau began to accumulate.

The research doesn’t explain Alzheimer’s completely. In addition to tau, another protein, called amyloid-beta, also accumulates in the brains of Alzheimer’s patients, but it isn’t subject to the same recycling process as tau. And no one really knows how these piles of molecular trash, known as plaques, lead to neurodegeneration.

Craik, Gestwicki, and Ravalin are hopeful that these discoveries will soon spark even more insight both into molecular recycling inside cells, how the process goes awry in neurodegeneration—and potentially how to keep such recycling going in older individuals.

“We’re still in the earliest stages of unraveling what’s really going on in Alzheimer’s disease, but it’s really exciting to finally put together some of the pieces of this medical puzzle,” said Craik.

Image credits: Elisabeth Fall (Gestwicki)