Protein PI31 Shows Neuroprotective Effects in Mice

Increasing levels of the protein PI31 shows neuroprotective effects in mice, researchers report.

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

Now, a new study identifies a novel strategy for preventing unwanted proteins from clogging synapses and ultimately congealing into protein plaques. The findings, published in PNAS, demonstrate that boosting levels of the protein PI31 can prevent neuronal degeneration, restore synaptic function, and significantly extend lifespan in fly and mouse models of rare genetic disorders similar to Parkinson’s.These results may also hold 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,” says Hermann steller, head of the Strang Laboratory of apoptosis and Cancer Biology at Rockefeller.

“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.”

It is tempting to blame everything on the protein aggregates that riddle Alzheimer’s and Parkinson’s brain. For decades, the field was dominated by the “amyloid hypothesis” which held that visible protein clumps, such as the beta-amyloid plaques and tau tangles characteristic of Alzheimer’s, were the direct cause of brain cell death. But as therapies that took aim at these plaques failed to produce notable improvements in the clinic, Steller began to wonder 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 focused so much on the aggregates, which our findings suggest are the result of the disease, not the cause.”

Prior work from the Steller lab has long hinted that neurodegeneration begins not with protein clumps, but with a failure to deliver proteasomes-the cell’s protein-degrading machines-to synapses. Proteasomes must travel long distances from the cell body to nerve endings, where