Strang Laboratory of Apoptosis and Cancer Biology at The Rockefeller University

Researchers Pinpoint Brain Process That May Lead to Amyloid Buildup

By Jacqui Ahearn | December 13th, 2019

Two recent studies focused on amyloid buildup, and identified a likely trigger for the degeneration that occurs at the cellular level.

Neurodegenerative diseases like Alzheimer’s and dementia are caused by specific protein clumps — like tau or beta amyloid. But researchers are still investigating how these proteins contribute to the cell death and brain changes associated with Alzheimer’s. Two recent studies focused on the accumulation of these proteins in the brain, and identified a likely trigger for the degeneration that occurs at the cellular level. Researchers determined that problems occur when there’s impairment in the system that transports proteasomes to cells. Proteasomes are molecular agents that break down proteins.

The first study, conducted by Rockefeller scientists, was published in the journal Developmental Cell. The second study, conducted in collaboration with Mary Beth Hatten’s lab, was then published in Proceedings of the National Academy of Sciences.

Proteasomes are formed inside the cell body of a neuron, after which they must be transported to nerve endings where the neuron connects to other cells. They assist cells in breaking down protein like amyloid.

If proteasomes can’t reach these nerve endings, the cell, unable to properly break down protein, struggles to function. This is where protein begins to accumulate, cause cell death and spur a series of events which ultimately lead to neurodegeneration.

Instead of being degraded by the cells, “damaged proteins hang around long enough to interact with other binding partners, form aggregates, and disrupt cellular function,” Hermann Steller, the Strang Professor at Rockefeller, said in a news release.

Amyloid or Proteasomes?

A large chunk of current Alzheimer’s research has focused primarily on beta-amyloid buildup as the main driver behind the disease. But with many amyloid drug questions and failures, scientists have begun wondering whether other factors in the brain may be better targets to fight off the disease — like tau or inflammation. For Steller, that target is proteasomes.

The first study looked at the proteasome transport system of fruit flies and identified a protein called PI31. PI31, the researchers found, plays an important role in loading proteasomes onto the cellular components that bring them to the nerve endings. PI31 also helps proteasomes move along. When PI31 is impaired, transportation of proteasomes between cells stops.

Further research proved that this is true not just for fruit flies but also for mice. The researchers believe that it may be a common mechanism across many species — but more research will need to be completed to see if it occurs in humans as well.

Following this finding, the team conducted a second study in which they generated mice in whom the PI31 gene was shut off in two groups of brain cells. In those cells, abnormal protein levels were accumulating at the neural tips and causing strange changes in the cells.

“Notably, these structural changes became progressively more severe with age,” Steller said. “Inactivation of PI31 in these neurons was reminiscent of the severe behavioral and anatomical defects we see in some human neurogenerative disease.”

Steller and his team are now working to determine if this discovery has any therapeutic applications, such as whether PI31 or the molecules which transport it could potentially be drug targets.

He believes that amyloid buildup or tau protein aggregation is not the cause of neurodegenerative disorders, but rather an additional symptom of the local cellular malfunction of proteasomes.

“Our work suggests that it really starts with a local defect in proteasomes, resulting in the failure to degrade proteins that are critical for nerve function,” Steller said.

For the next steps, Steller and his team are investigating ways to stimulate transportation of proteasomes out to the nerve endings.

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