This study shows that interferon-driven induction of the immunoproteasome subunit PSMB8 in neurons reduces proteasome β5 catalytic activity, causing accumulation of the glycolytic regulator PFKFB3. PFKFB3 accumulation shifts neurons from the pentose phosphate pathway to glycolysis, lowering NADPH/GSH, increasing ROS and lipid peroxidation, and sensitizing neurons to ferroptosis. Neuron-specific genetic deletion or pharmacologic inhibition of PSMB8 or PFKFB3 protected neurons in vitro and in mouse EAE models, highlighting new neuroprotective strategies for MS.
0:00Welcome to Base by Base, the paper cast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. So, When we think about neurodegenerative diseases, especially multiple sclerosis, we usually tend to visualize a battlefield.
0:16Right, yeah. That's the classic way to look at it. Exactly. I mean, we know the immune system goes rogue, right? It crosses the blood brain barrier and just causes the severe inflammation. But there has always been this fundamental mystery at the heart of the whole process.
0:31Oh, totally. The actual mechanism of the damage. Right. Like we see the crossfire, but how does that immune crossfire cause the actual brain cells, the neurons themselves, you know, to die, what really happens when a neuron tries to defend itself against inflammation, but accidentally triggers its own metabolic collapse?
0:49Yeah, it really is just this devastating paradox. I mean, we've mapped out the immune side of that battlefield quite thoroughly over the years. We have. But the neuron's actual internal response to that hostile environment.
1:01That's been, well, largely obscured. almost like a black box. I was trying to visualize what's happening inside the cell, you know, to really wrap my head around it. And I kept coming back to his city's waste management system.
1:13Oh, that's a good way to look at it. Right. So let's say you have an internal recycling center in the neuron, a structure called the codisum. It's constantly taking in damaged proteins, breaking them down, basically keeping the streets clean.
1:24Yeah, standard maintenance Exactly. But during a crisis, like severe inflammation. The city kind of panics, it swaps out its regular trash compactors for specialized wartime machinery. But, and here's the question.
1:37What if that new machinery is fundamentally mismatched for the city? What if it's so slow that toxic waste begins to build up, eventually causing a catastrophic citywide power failure? That analogy actually captures the exact dynamic we're exploring today, because the destruction of the neuron isn't just a direct result of the external attack.
1:59It is the neuron's own defensive adaptation to that attack that ultimately seals its fate. The idea that a cell's own defense mechanism is what kills it is just staggering to me. I really want to dive into how we actually know this is happening, because peering inside a single neuron during an immune storm just seems, well, impossible.
2:22It definitely took some remarkable engineering to prove it, that's for sure. Well, today we celebrate the work of the team led by Manuel A. Freeze at the Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center, Hamburg, Eppendorf, along with their global collaborators.
2:36They have advanced our understanding of how inflammation directly disrupts neuronometabolism to drive neurodegeneration. Yeah, their work represents a massive step forward for the field. I mean, if we look at the broader context, multiple sclerosis is a major inflammatory and neurodegenerative disease affecting young adults.
2:55Right, and it's driven by those auto-reactive T cells, right? Exactly. These T cells infiltrate the central nervous system, and once those immune cells are inside the brain and spinal cord, they don't just sit there.
3:06They release a storm of inflammatory signals. And this persistent neuroinflammation isn't just an MS problem, is it? No, not at all. It's actually a hallmark of aging in general. And it's present in other neurodegenerative diseases like Alzheimer's and Parkinson's too.
3:20So what's the primary signal driving this specific response? Like, is there one dominant alarm bell ringing? There is, yeah. The most prominent driver in the scenario is a really potent cytokine called Interfere on Bama.
3:33Okay, let's unpack this. We know these T cells infiltrate the brain. And we know they flood the environment with Interfere on Gamma, but I'm still missing the bridge between that alarm bell and the neuron actually dying.
3:46Right, the missing link. Yeah. Like, why don't the neurons just hunker down, weather the storm and wait for the immune flare up to pass? Well, to understand why they can't just wait it out, we have to look at the concept of proteostasis.
3:58Okay, pretty astasis. Yeah, it's the continuous, really delicate balancing act of protein creation and protein degradation inside any cell. As you mentioned earlier with the waste management idea, cells use a complex called the produceum to degrade proteins.
4:13And specifically, the catalytic core of this whole thing is known as the 20 S core particle. So this 20 S core is basically the actual shredder blade of the trash compactor. Exactly. The shredder blade.
4:25And in dividing immune cells, when they get hit with an inflammatory signal, like interfuron gamma, they do something highly functional. What do they do? They swap out their standard produce some subunits for what we call immunoproduce some subunits.
4:39Wait, really? So immune cells deliberately change their own recycling centers during a crisis. Why would they do that? They do it to process proteins differently. An immunoproteism is specifically designed to chop proteins into very specific peptide lengths.
4:53Oh I see. Yeah, and then those little pieces are shuttled to the surface of the cell and presented as antigens to alert the rest of the immune system. It's a critical adaptation for rapid response and immune communication.
5:05That makes total sense for an immune cell. But neurons are postmitotic. Right. don't divide? Yeah, they don't divide. They don't hunt down pathogens, and they live for decades with incredibly complex structures.
5:16And that right there is the baseline context of this entire deep dive. We are exploring how these non-dividing highly specialized neurons react to those exact same inflammatory signals. So do they also try to build immunoprote sums?
5:32That's the question. And if they do, what are the consequences for a cell that isn't designed to present antigens in the 1st place? But testing that seems like a logistical nightmare. I mean, if the brain is swarming with immune cells and inflamed supporting cells and all this debris, how do you even see what the neuron itself is doing?
5:49It is an incredibly noisy environment. To isolate the neuron's response, the research team used a specific animal model called experimental autoimmune encephalomyelitis, or EAE in mice. And that's the gold standard model for MS.
6:04Exactly. But their real innovation here was a protium tagging technique to cut through all that noise. Oh, how did that work? They cross neuron-specific snap 25 cream ice with LSL R26 Mitter S star mice.
6:15Okay, I'm going to need you to translate that genetics for me. What does that cross actually achieve in the mouse? Fair enough. Essentially, the meta star is a mutant enzyme. When it's expressed, it can incorporate a non-canonical amino acid into newly synthesized proteins.
6:31But because they use the Cree system linked specifically to Snap 25, this mutant enzyme is only turned on inside the neurons. Ah, I see. So it's almost like a, well, giving a special invisible ink only to the factory workers.
6:47neurons, yeah. the neurons inside this chaotic inflamed city. So when you extract the tissue and use a chemical reader later, you see exactly what proteins those factory workers built. You can completely ignore everything built by the rioters, the immune cells outside.
7:01That invisible ink analogy is spot on. By using click chemistry to pull out only the newly synthesized proteins containing that specific tag, they bypass the noise of the neuroinflammation entirely. That is so clever.
7:14It really is. they didn't stop there. They paired this with RNA sequencing of neuronal nuclei to map gene expression, and a probe called sci-fi apoximisin. Oh, does that probe do? It physically tracks the speed and activity of the neurons recycling centers.
7:27They even used melody mass spectrometry imaging to map the physical buildup of specific metabolites in the spinal cord. Wow, they threw an absolute arsenal at this. So when they finally read the invisible ink, What did they find the neurons were actually building?
7:41Well, here's where it gets really interesting. I'm ready. They found that during this MS-like inflammation, the Interferon Gamma forces the neurons to alter their recycling centers. The neurons start expressing an immunoproteisum subunit called PSMB8.
7:56And this PSNB 8 replaces the normal Shredder Blade, which I think is called PSNB 5. Correct. The neuron swaps its standard subunit for the wartime subunit. Hold on. I'm confused here. If this PSMB 8 subunit is a wartime upgrade that makes immune cells faster, better at surviving and great at presenting antigens, why does it break the neurons factory?
8:19It's great question. Like, why does the exact same biological part have the exact opposite effect depending on the cell type? It comes down to structural and functional mismatch. An immunoprotisome in a T cell is optimized to cleave proteins into those specific peptide links for antigen presentation.
8:36But it is not designed for the bulk daily degradation of the highly specialized, complex structural proteins that a neuron relies on to maintain its massive axon and its synapses. Oh, so the neuron is trying to stuff a complex structural beam into a shredder designed to make tiny uniform puzzle pieces.
8:56Exactly. So when PSME8 integrates into the neuron's produceum, it drastically decreases the overall catalytic activity for what the neuron actually needs to degrade. The trash compactor slows down to a crawl.
9:07Wow. Yeah, the adaptation that optimizes an immune cell ends up completely crippling the post-mitotic neuron. So the wartime machinery is just totally incompatible with the factory. And because the compactor slows down, the trash must start to pile up.
9:20It does, but the researchers found it wasn't just random cellular debris piling up. A very specific, highly critical metabolic enzyme begins to accumulate, purely because the produce sum is no longer degrading it fast enough.
9:33That enzyme is called PFKFB3. Okay, PFKFB 3. What does that enzyme normally do in a healthy neuron? In a healthy neuron, PFKFB 3 is kept at very low levels. The active crotisum constantly shreds it. And this is vital because neurons rely heavily on a metabolic route called the Pentos phosphate pathway or the PPP.
9:55The PPP. Yes. And the PPP is essential because it generates antioxidants for the cell. So if this enzyme builds up, it must be redirecting something. Is it acting like a train switch operator on the metabolic tracks?
10:07That's a brilliant way to conceptualize it. PFKFB 3 produces a molecule that allysterically activates another enzyme and that drives glucose down the glycolytic pathway instead. So it essentially flips the tracks.
10:18Exactly. Accumulated PFKFB3 forces the neuron's metabolism away from the protective pentose phosphate pathway and shunts everything into heavy glycolysis. But why is leaving the pentos phosphate pathway so deadly for the neuron?
10:32Like, what's the immediate consequence of flipping that switch? It all comes down to the sudden loss of antioxidants? The PPP creates crucial molecules specifically NADPH and glutathion? And glutifyone is important.
10:45Lutithion is basically the biological fire extinguisher of the cell. It neutralizes reactive oxygen species. But normal cellular processes are constantly producing those reactive oxygen species, right?
10:58Like tiny metabolic sparks. Constantly. Especially in a highly active cell, like a neuron. So if you flip the metabolic switch and shut down the PPP, the neuron supply of those fire extinguishers just plummets.
11:11Yeah, those tiny metabolic sparks are no longer neutralized. And so they ignite the cell's structural lipids. The fats that make up the cell membrane. Yes. The structural lipids undergo massive oxidation.
11:23They literally rust and break apart because they are stripped of their protective antioxidants. sounds terrifying. It is. This leads to a very specific catastrophic event called ferreptosis, which is a type of cell death driven by toxic lipid peroxidation.
11:36The researchers proved this by showing that neurons expressing PSNBA had massive spikes and lipid peroxidation. That made them incredibly vulnerable to glutamate excitotoxicity and ultimately resulted in ferreptosis.
11:52It's just a tragic domino effect when you lay it all out like. really is. So the immune system causes inflammation. The neuron tries to adapt by building an aminoproteaseum to handle the stress, but that aminoproteaseum is fundamentally the wrong shape for the neuron's trash, so the recycling center jams.
12:09PFKFB 3 piles up. It flips the metabolic switch away from antioxidant production. The neuron runs out of glutothion. Its membranes basically rust, and it dies. It is a devastating sequence, but mapping the cascade is really only half the battle.
12:24Right, because you want to stop it. Exactly. The researchers wanted to see if they could stop those dominoes from falling in the 1st place. And the Inviva data, the results from the living mice are incredibly compelling.
12:34How did they manage to intervene in such a complex cascade? Well, they approached it from 2 different angles. First, they use a genetic approach. They created a mouse model, where they specifically deleted the gene for PS of B 8, that faulty immunoprodisum subunit only in the neurons.
12:50So even when the inflammation alarm bells were ringing, the neurons were physically incapable of building that incompatible trash compactor. Right. And when these mice were subjected to MS like inflammation, their disease severity was significantly reduced.
13:04Wait, really? Yeah, they saw less neuronal loss, preserved synapses in the spinal cord, and reduced axonal degeneration. The neurons survived the immune storm simply because their internal metabolism remained intact.
13:16That's incredible, but we obviously can't just edit the genes of living human patients to remove a produce and subunit. Did they test anything pharmacological? They did. They used a systemic drug called ONX 0914, which inhibits the immunoprodisum.
13:30And did that work? It did. Treating the mice with this drug also reduced disease severity. But perhaps even more elegantly. They targeted the metabolic switch itself. They used a drug called PFK 158 to inhibit that accumulating PFKFB3 enzyme.
13:46Oh, that's fascinating. So even if the produceum was broken and PFKFD3 was piling up in the streets, the drug basically incapacitated the switch operator. Exactly. It forced metabolism back to the protective pentos phosphate pathway.
14:00And the neurons survived. The protective effect was perfectly mirrored. Less disease severity, fewer dying neurons, drastically reduced lipid proxidation. By chemically inhibiting the metabolic switch, they completely shielded the neurons from the immune system's crossfire.
14:17So what does this all mean for how we actually treat these diseases? Because it sounds like we are looking at a massive clinical paradigm shift here. We really are. Think about the current landscape of therapies for multiple sclerosis right now.
14:29Virtually all of our highly effective disease modifying therapies are designed to suppress or modulate the peripheral immune system. Right. We try to stop the T cells from attacking or stop them from entering the brain.
14:41It's like trying to stop a siege by negotiating with the invading army or just reinforcing the outer gates. But we're doing very little to fortify the castle from the inside while the walls are actively crumbling.
14:53That's a perfect analogy. These findings present a tangible opportunity for true neuroprotective therapies. Treatments that target the brain intrinsically, building neuronal resilience against inflammatory stress regardless of what the immune system is doing.
15:09Because if we can keep the neuron's metabolic engine running correctly, it can survive a hostile environment. And the implications have to go way beyond multiple sclerosis, right? I mean, we mentioned earlier that neuro inflammation isn't just an MS problem.
15:23It's a universal hallmark of neurodegenerative diseases. We know that neuroinflammation and produce some dysfunction are early markers of Alzheimer's and Parkinson's disease. They often appear long before the severe cognitive or motor symptoms even manifest, don't they?
15:38Yes they do. So if a brain is chronically inflamed for years, whether that's from rogue T cells and MS or, you know, toxic protein plaques in Alzheimer's, the neurons might be slowly starving themselves of antioxidants by stubbornly switching to this immunoproteisum.
15:56It is a highly compelling hypothesis. This PSMB 8 induced tipping point where inflammation forces the produce sums of falter and alters cellular metabolism. It might be a unifying mechanism across multiple forms of neurodegeneration.
16:09That completely reorients how we might approach neuroprotection on a global scale. really does. As incredible as this is, I do want to push back a little bit on the limitations. We've talked about shutting down this metabolic switch with drugs like PFK 158.
16:22But earlier, you said immune cells naturally use the immunoportisome and actually rely on these pathways. So if we just give a patient a systemic drug that shuts those down everywhere in the body, wouldn't that severely compromise their immune system?
16:35You've hit on the major clinical caveat there. And the researchers are very transparent about this. The pharmacological drugs used in the study, ONX 091 Tour and PFK 158. They do suppress the immune system globally.
16:49If you shut down the immunoproteisum everywhere, immune cells can't process antigens properly. So you might save the neurons, but you'd completely cripple the patient's ability to fight off like a standard viral infection.
17:02Precisely the risk. While patients with an autoimmune disease like MS already tolerate some level of targeted ammunosuppression, broadly suppressing antigen presentation just isn't ideal. Especially not long term.
17:15Right, and it's certainly not a viable long-term strategy for a broader application in diseases like Alzheimer's. Are there any other blind spots in the mechanism we should be aware of? Well, there is an interesting biochemical wrinkle.
17:26When they blocked the pentos phosphate pathway, it drastically reduced the antioxidants, but it didn't completely eradicate all the glutophion in the neurons. Oh, really? Meaning the neurons must have some backup systems or alternative pathways for generating antioxidants that we just haven't fully mapped out yet.
17:44Exactly. Biology rarely relies on a single point of failure if it can avoid it. Yeah, that makes sense. So while this mechanism is clearly a major driver of ferreptosis, it's operating alongside other complex cellular networks.
17:58The immediate next steps for this research really have to be about precision. We need to figure out how to get the medicine only to the factory workers, not the entire city. Yes. Future therapeutics need to explore targeted delivery systems.
18:11For instance, utilizing targeted protein degraders, like ProTax, or nanoparticle delivery systems that solely inhibit PSMBA or PFKFB3 inside the neurons. Without compromising the systemic immune response.
18:24Exactly. Now that the target has been clearly validated, solving the delivery mechanism is the next great hurdle. It's just an incredible piece of detective work. Tracing a whole body immune response down to a single faulty gear in a cellular trash compactor, which leads to a metabolic train wreck, and ultimately the rusting of the cell membrane.
18:41It's quite a journey. It really highlights a fundamental, almost tragic truth of biology sometimes. It's our own defensive adaptations that leave us most vulnerable. The neuron tries its hardest to act like an immune cell to survive the stress, and it pays the ultimate price for that mismatch.
18:58It proves that the neuron is not just a passive victim in neurodegeneration. Its internal machinery is actively involved in its own demise, but more importantly, it proves that this internal machinery is targetable.
19:12We have a new pathway to intervene. Let's bring this all together for you. If you're going to take away one core insight from this deep dive. It is this. Inflammation in multiple sclerosis forces neurons to alter their cellular recycling centers, causing a metabolic traffic jam that depletes essential antioxidants and triggers cell death.
19:30By blocking the specific metabolic switch, we can shield neurons from the immune system's crossfire. It's a completely new way of looking at neuronal survival. Exactly. What does this mean for the future of treating neurodegenerative diseases, where protecting the brain's internal metabolism becomes just as important as calming the immune system, attacking it?
19:50It's definitely something to think about. This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description.
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