Ivan Kairatov is a leading biopharma expert whose work sits at the intersection of molecular innovation and neurodegenerative research. With years of experience in research and development, he has dedicated his career to untangling the complex web of protein interactions that govern brain health. In this conversation, we explore a groundbreaking study from the Duncan Neurological Research Institute that finally answers one of the most perplexing questions in neuroscience: why do certain diseases, like spinocerebellar ataxia type 1, devastate specific brain regions even when the underlying toxic proteins are found throughout the entire body?
The discussion delves into the intricate choreography of protein partnerships, specifically the relationship between ATAXIN-1 and its stabilizer, Capicua. We examine how different variants of these proteins—CIC-Long and CIC-Short—dictate whether a cell survives or succumbs to damage, and how these findings reveal a surprising link between rare ataxia and more common conditions like Alzheimer’s. By looking at the unique vulnerabilities of the cerebellum and the lungs, the interview sheds light on a future where therapies are tailored not just to a disease, but to the specific molecular complexes of the affected tissue.
Although mutant proteins like ATAXIN-1 are found throughout the brain and even in organs like the heart and liver, the damage in SCA1 is largely confined to the cerebellum and brain stem. What have we discovered about why certain tissues are so uniquely vulnerable to this overactive protein while others remain seemingly untouched?
For a long time, the scientific community was puzzled by the selective nature of neurodegeneration, but we have finally found that the secret lies in the company a protein keeps. In our study of spinocerebellar ataxia type 1, or SCA1, we observed that the mutant ATXN1 protein doesn’t act alone; its toxicity is heavily dependent on its partner, a protein called Capicua, or CIC. While ATXN1 is expressed in many places, the cerebellum—the region responsible for balance and coordination—happens to have the highest levels of CIC, creating a perfect storm for damage. When the mutant ATXN1 becomes overactive and begins to accumulate, it hijacks these high levels of CIC, leading to the slurred speech, swallowing difficulties, and progressive loss of coordination that characterize the disease. It is a matter of regional abundance where the high concentration of specific partner proteins makes the cerebellum a “sweet spot” for this molecular catastrophe to unfold.
The research highlights a “lookalike” protein known as ataxin-1-like, or ATXN1L, which seems to have a very different role than its counterpart. How does the presence of this similar protein complicate the biological landscape, especially regarding non-neurological symptoms?
It is fascinating how two proteins can look so much alike yet lead to such vastly different biological outcomes when they are missing or disrupted. While the mutant ATXN1 causes the devastating movement issues of SCA1, we found that eliminating its cousin, ATXN1L, in animal models led to an entirely different set of tragedies, including perinatal mortality where newborns die shortly after birth. These subjects often suffered from severe lung defects and hydrocephalus, which is a dangerous and abnormal buildup of cerebrospinal fluid within the brain’s cavities that causes significant damage. This tells us that ATXN1L is essential for the very basic plumbing and respiratory development of the body. It highlights the fact that these similar proteins are not redundant; instead, they have carved out specialized roles in different tissues, meaning a therapy that ignores these distinctions could inadvertently cause life-threatening issues in the lungs or brain fluid regulation.
The study identifies two distinct forms of the partner protein Capicua—CIC-Long and CIC-Short. Could you walk us through how these two forms function and the specific consequences that occur when one is removed while the other remains?
Understanding the distinct roles of CIC-Long and CIC-Short was a major “aha” moment for the team because it proved that these forms are not interchangeable. When we genetically engineered mice to lack only CIC-Short, we saw heartbreaking results: many died early in life, struggling with poor growth and developmental problems, particularly in the lungs and through the accumulation of fluid in the brain. On the other hand, mice that lacked only CIC-Long survived, but they were far from healthy; they developed significant behavioral problems, including hyperactivity, movement deficits, and profound learning and memory difficulties. These findings were quite visceral to witness, as they clearly showed that CIC-Short is tied to physical survival and organ development, while CIC-Long is the primary driver for cognitive and motor functions. It proves that the subtle differences at one end of the protein sequence actually dictate entirely different life paths for the organism.
It was noted that simply lacking the ATXN1 protein altogether doesn’t cause ataxia, but instead leads to symptoms resembling Alzheimer’s disease. What does this tell us about the delicate balance required for brain health?
This is one of the most compelling twists in our research because it shows that having too little of a protein can be just as dangerous as having a toxic, overactive version. When ATXN1 is missing, we don’t see the coordination loss found in SCA1, but we do see mice developing learning and memory deficits that are the hallmark of conditions like Alzheimer’s. Even more striking was the discovery that knocking out ATXN1 increases the production of amyloid beta, the very substance that clogs the brains of Alzheimer’s patients, specifically affecting the cortex and hippocampus. It suggests that ATXN1 normally plays a protective role in these regions, keeping amyloid levels in check. This means that in our quest to treat SCA1 by reducing mutant ATXN1, we must be incredibly careful not to push the levels so low that we inadvertently trigger an Alzheimer’s-like state in the patient’s cortex.
The study reveals a very specific “pairing” system where CIC-Long prefers ATXN1 and CIC-Short prefers ATXN1L. How does this specialized interaction explain why the loss of certain proteins affects specific organs like the lungs or the cerebellum more than others?
The specificity of these pairings is the key that unlocks our understanding of tissue-wide vulnerability. We discovered that CIC-L and ATXN1 are essentially “best friends” in the brain, while CIC-S and ATXN1L are the dominant pair during critical stages like lung development. Because CIC-L prefers to bind with ATXN1, the stability of the CIC-L protein is heavily dependent on ATXN1 being there; if ATXN1 is gone or faulty, CIC-L essentially falls apart, leading to those hyperactivity and memory issues we discussed. Conversely, because ATXN1L is highest during lung development alongside high levels of CIC-S, any disruption to that specific partnership leads to the lethal respiratory failures we observed. This molecular choreography explains why a mutation in one protein can be a death sentence for a lung cell but merely a nuisance for a cell in a different part of the brain where its preferred partner is less abundant.
Given that these protein forms vary depending on the stage of development and the specific brain region, how does this change the way we should approach drug development for neurodegenerative diseases?
This research is a call to move away from “blunt instrument” drugs and toward more “surgical” molecular therapies. If we know that the toxicity in the cerebellum is driven by the specific partnership between overactive ATXN1 and CIC-Long, our goal should be to target that specific complex without touching the CIC-Short protein that is so vital for lung health and brain fluid balance. By understanding the relative abundance of these forms, we can start to predict which patients might be more vulnerable to certain side effects based on their developmental stage or the specific progression of their disease. We are entering an era of “complex-specific” medicine where we don’t just target a gene, but we target the specific social circle of proteins that are causing the trouble in a specific neighborhood of the brain. It offers a much more hopeful and precise pathway for treating conditions that were once thought to be universally untreatable.
What is your forecast for the future of treatment for rare neurological disorders in light of these findings?
I believe that in the next decade, we will see a paradigm shift where we stop treating neurodegenerative diseases as systemic failures and start treating them as region-specific protein imbalances. Our discovery that subtle differences in protein abundance can dictate whether a tissue lives or dies will lead to a new generation of stabilizers and inhibitors that can protect the cerebellum while leaving the cortex and lungs completely unaffected. I forecast that we will soon have diagnostic tools that can map a patient’s specific protein “landscape,” allowing us to intervene with therapies that are timed to their developmental needs. Ultimately, this study has provided the roadmap for precision neurology, and I am confident that by targeting these specific protein partnerships, we will finally be able to offer meaningful relief to those suffering from SCA1 and perhaps even slow the progression of more common ailments like Alzheimer’s.
