One fundamental feature of neurodegenerative diseases is a breakdown in communication. 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."
Amyloid plaques: cause or symptom?
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 significant 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 consequence 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 they routinely clear out damaged proteins at synapses to keep neurons communicating. If proteasomes fail to arrive, waste builds up and communication breaks down. In that case, therapies aimed only at clearing plaques would hit the field too late in the game—the real solution would be fixing the transport system that delivers the cleanup crew before congestion accrues.
In a 2019 paper, Steller identified a promising lead for fixing that transportation system: PI31, a protein that acts as an adaptor responsible for loading proteasomes onto cellular motors for the journey to the synapse, and assembles them upon arrival. Without PI31, he found that transport stalls, protein waste accumulates, and aggregates form. Flies and mice without PI31 begin to show signs of neurodegeneration, and mutations that lead to loss or reductions in PI31's normal function, as well as genes coding for related proteins, have since been implicated in a number of neurodegenerative diseases.
"Variants of the gene coding for PI31 are found in Alzheimer's patients. They're found in ALS patients. Patients with these same variations are sometimes diagnosed with Parkinson's," Steller says. "We had seen it in flies; we had knocked it out in mice. So we wanted to know: could we use it for a cure?"
Towards a new therapy
To test whether boosting PI31 could ward off neurodegeneration, Steller turned to a rare genetic disorder caused by mutations in the gene FBXO7. These mutations lead to an early-onset, Parkinson's-like syndrome in humans, giving the model clinical relevance. Just as importantly, FBXO7 is tied to PI31: when FBXO7 is lost, PI31 levels fall.
Steller's team began with fruit fly models, where they demonstrated that inactivating the fly equivalent of FBXO7 caused severe motor defects and disrupted proteasome transport, in line with the expected Parkinson's-like symptoms. When they added back extra copies of PI31, these symptoms were largely reversed, as the proteasomes began moving smoothly again.
The researchers then moved onto FBXO7-deficient mice, where they found that even modest increases in PI31 levels strongly suppressed neuronal degeneration, preserved motor function, and improved overall health. In some cases, the lifespan of the mice was extended nearly fourfold. PI31 also cleared away abnormal tau proteins, a hallmark of Alzheimer's disease.
Together, the results demonstrated an overexpression of PI31 can keep proteasomes on track, thereby preventing many of the hallmarks of neurodegeneration in mice and fruit flies. "The degree to which we can rescue the various defects in mice is remarkable," Steller says.
The next step is to test whether PI31 can preserve cognitive function in aging mice, with the hopes of then moving toward preclinical development of therapies for humans.
In a recent preprint , Steller's lab collaborated on a project that showed that humans with rare mutations in the PI31 gene suffer from a spectrum of neurodegenerative conditions. These findings indicate that a PI31 therapy could target rare disorders caused by FBXO7 or PI31 deficiency in the small number of humans who suffer from these conditions. In time, Steller suspects that lessons learned from treating these rare conditions could yield broader strategies for slowing age-related cognitive decline and tackling more common diseases, such as Alzheimer's.
"We're extremely excited that this is relevant beyond our fly and mouse models of FBOX7," Steller says. "The science implies that our findings may potentially, down the road, allow us to slow down cognitive decline as we age."
