Boosting PI31 Protein Prevents Synaptic Clogging and Extends Lifespan

A fundamental feature of neurodegenerative diseases is a breakdown in communication. Even before brain cells die, the machinery that keeps neurons in touch-by clearing away protein waste at the synapses-starts to fail. When cleanup falters, connections between brain cells are impaired, and the signals responsible for reasoning, language, memory, and basic bodily functions are progressively disrupted.

A new study identifies a strategy for preventing unwanted proteins from clogging synapses and forming protein plaques. Published in PNAS, the findings demonstrate that boosting levels of the protein PI31 can prevent neuronal degeneration, restore synaptic function, and substantially extend lifespan in fly and mouse models of rare genetic disorders similar to Parkinson’s. These results may also offer promise for treating Alzheimer’s and slowing age-related cognitive decline.

“A number of diseases-Alzheimer’s, Parkinson’s-are, in fact, diseases of synaptic dysfunction, at least initially. Now that we’ve shown how to eliminate unwanted proteins at the synapse, we hope this will lead to a revolution in treating common age-related disorders.”

hermann Steller, head of the Strang Laboratory of Apoptosis and Cancer Biology at Rockefeller

Amyloid plaques: cause or symptom?

It’s tempting to blame protein aggregates that riddle Alzheimer’s and Parkinson’s brains. For decades, the field was dominated by the “amyloid hypothesis,” which held that visible protein clumps, like beta-amyloid plaques and tau tangles in Alzheimer’s, directly cause brain cell death. But as therapies targeting these plaques failed in clinical trials, Steller began to question whether protein clumps were a symptom, rather than a cause, of neurodegeneration.

“It’s not good to have protein clumps,” Steller says. “But people have found that you can have a lot of plaques without necessarily having a lot of neurodegeneration. And conversely, you can have neurodegeneration without a lot of plaques.”