Jose Rodriguez and Hermann Steller's recent publication points to a possible new therapeutic target in the fight against Parkinson's, Alzheimer's, and related disorders. (Credit: Lori Chertoff)
Neurodegenerative diseases such as Alzheimer's and Parkinson's feature telltale protein plaques that clog the brain, but attempts to clear those aggregates have failed to meaningfully improve outcomes for patients. That could be because protein clumps are a consequence, not a cause, of neurodegenerative disease. Hermann Steller's lab has demonstrated that a major culprit may be a slowdown in the transport system that delivers proteasomes, the cell's cleanup machines, to synapses. Following this logic, therapies may be more effective if aimed at increasing the activity of proteasomes at synapses, rather than removing the plaques that build up because of this malfunction.
In a new study, Steller's team reports that boosting levels of PI31, a protein that keeps proteasomes active and on track, addressed the hallmarks of neurodegeneration in fruit flies and mice. The treatment preserved motor function, extended lifespan fourfold in some cases, and even cleared away the accumulation of abnormal tau proteins characteristic of Alzheimer's disease. We asked Steller what this breakthrough reveals about the origins of neurodegenerative disease, and how his findings could pave the way for new therapies.
How did you first come across the protein that regulates this cleanup system?
Steller: If you go back 15 years, it's really a basic science discovery of how proteins are degraded in a regulated manner. We discovered, in an unbiased way, the dual role of the protein PI31. It loads proteasomes onto cellular motors so they can travel all the way down to the synapses and, once they get there, it also helps assemble them into the fully functional machine that breaks down damaged proteins. Then, in 2019, we published a paper that showed that when you knock out PI31 in mice, that loss leads to the hallmarks of neuronal degeneration, including axon degeneration, neuronal loss, and progressive spinal and cerebellar neurological dysfunction.
Our newest paper focuses on what happens when you rescue PI31 function. We've now shown that even modest overexpression of PI31 helps. This suggests that neurodegeneration may be characterized less by plaques than by malfunctions in the system that clears proteins at synapses.
This sounds like a powerful reframing of our understanding of underlying causes of neurodegenerative disease.
Steller: All of these diseases-Alzheimer's, Parkinson's, ALS-may be called neurodegenerative diseases, but they're actually all diseases of synaptic dysfunction, at least initially. They all start when communication between nerve cells is affected, before any overt neuronal degeneration.
People have focused so much on the aggregates-such as beta-amyloid in Alzheimer's-but our work indicates those aggregates are a consequence of the disease, more than the underlying, primary cause. Sure, they're not helpful. But those clumps won't be there if the proteasome does its job. So we began focusing on what causes the proteasome to fail to clear proteins at the synapse, and whether we can restore that system. I see it as a new approach to thinking about age-related neurodegenerative disease.
Do these findings confirm that PI31 deficiency is a cause of neurodegeneration?
Steller: It's more complicated than that. There is a whole spectrum of PI31 variants. Variants that completely inactivate the gene result in stillbirth in both humans and mice. Variants that retain some functioning PI31 cause childhood onset of Parkinson's-like symptoms, and the more gene function they retain, the later the onset of the disease. Variants of the gene coding for PI31 are also found in Alzheimer's patients. They're found in ALS and Parkinson's patients.
But, with the exception of rare genetic disorders, we think it's more of a predisposition. A mutation that causes PI31 deficiency may make you more likely to get a neurodegenerative disease, but something else has to happen. We know that the pathway that clears proteins from the synapse is affected by environmental factors. If we don't sleep enough, or we have unhealthy lifestyles, the pathway may not work as well. In fact, PI31 is more active when we sleep, and that's probably when most of the protein clearance at synapses takes place.
What still remains to be discovered about PI31's role in neurodegeneration?
Steller: My whole lab is now, in one way or another, focused on understanding this pathway. Because it's not just about PI31 and how to overexpress it-we're also asking questions about the regulation of proteasome transport. The interaction between PI31 and the proteasome is a little like loading children onto a school bus. The proteasomes hop on, and they get shuttled down, and then somehow, they get released. But we currently only understand the shuttling part. How do they get unloaded at the synapse? Do all of them get unloaded? How do they get loaded back up? How is this regulated, and why does the body invest so much energy in moving proteosomes about?
Our speculation is that it's a kind of troop rotation. You send troops out and then back to recover, and our working model is that that R&R period is significant for helping to repair or eliminate faulty proteasomes. I think the whole process of "recycling" proteasomes between different cellular compartments is probably very, very important.
We also don't understand what exactly, at the molecular level, fails at synapses when proteins are overwhelmed. There's a lot of basic science still to be done, with likely medical implications. We are working hard to understand what changes at the synapse when proteasomes fail to clean it up, and what we find might yield additional therapeutic targets.
Gene therapy has been floated as a strategy for neurodegenerative diseases for some time. Could your findings translate into a gene therapy?
Steller: Gene therapies for a number of neurological disorders are underway or already FDA-approved; a number of studies are underway for gene therapy for congenital hearing loss and various other diseases, all with promising results. Because they have the right targets. The reason that gene therapy has not always historically worked in humans is that you need to have the right gene.
When it comes to gene therapy targeting PI31, I'm optimistic that we have the right gene. And we haven't seen any harmful effects from elevated levels of PI31 in mice, so far. At the same time, gene therapy isn't the only potential approach for overexpressing PI31. Hopefully we could also pharmacologically target this, down the road.
