Written by: Juan Mato
Edited by: Brenna Saladin
This piece was written in collaboration with the 2025 ComSciCon-MI Write-A-Thon.
Spinocerebellar ataxia type 3 (SCA3) is the most common inherited form of ataxia– a disordered loss of motor coordination. This rare, progressive disorder stems from a genetic error in the DNA sequence encoding the ATXN3 protein. Instead of functioning normally, this mutant protein becomes toxic, gradually damaging nerve cells.
For decades, research on SCA3 has focused mainly on the central nervous system—the brain and spinal cord—because the disease’s hallmark symptom is muscle incoordination. But, over half of patients also suffer from peripheral neuropathy, which affects nerves outside the brain and spinal cord. These patients experience burning pain, numbness, or reduced sensation in their limbs. Such symptoms further worsen mobility and quality of life, yet this side of the disease has been relatively neglected in research.
Our recent study set out to close this research gap. We used innovative mouse models to uncover how peripheral neuropathy develops in SCA3 and established sensory neurons—the nerve cells that detect touch, temperature, and pain—as important targets for future therapies that could provide patients with SCA3 much-needed relief.
Building Better Models
Studying peripheral neuropathy in SCA3 has been challenging because researchers previously lacked robust animal models that faithfully mimic this condition. To tackle this, our lab investigated features of peripheral neuropathy in two types of genetically engineered mice:
- Knock-In (KI) mice, which have the harmful ATXN3 mutation “knocked- into” their DNA.
- Knock-Out (KO) mice, which have had the ATXN3 gene deleted from their DNA.
These models let researchers separate whether neuropathy is caused by the toxic effects of the mutant protein (represented by the KI mice) or simply by losing ATXN3’s normal role in the cell (represented by the KO mice).
Signs of Nerve Trouble
In the KI mice, we saw clear evidence of nerve dysfunction. Electrical tests showed reduced signal strength and slower conduction in sensory and motor nerves, mirroring problems seen in patients. Behaviorally, the mice developed difficulties with balance, coordination, and sensitivity to touch and temperature. Microscopic analysis revealed loss of myelinated fibers—the insulated nerve fibers that transmit signals quickly throughout your body—and damage to tiny pain-sensing fibers in the skin. This small fiber neuropathy helps explain why patients feel burning pain and/or numbness. Importantly, none of these issues appeared in the KO mice, confirming that neuropathy stems from the toxic gain of function of mutant ATXN3, not from the absence of the normal protein.
A Precision Strike on Sensory Neurons
To dig deeper, we created a conditional version of the KI mouse (cKI) mouse that can be genetically manipulated to “switch off” mutant ATXN3 in specific cell types. We utilized this novel mouse to selectively silence the toxic gene in sensory neurons while leaving it active everywhere else in the nervous system.
Our results gave us a lot to be excited about!. Mice with mutant ATXN3 silenced specifically in sensory neurons showed:
- Improved nerve conduction in sensory nerves
- Better balance and coordination on movement tests
- Partial recovery of temperature and touch sensitivity
However, motor nerve function did not improve, highlighting that motor symptoms in disease involve other cell types as well. Still, this partial rescue strongly pointed to sensory neurons as key players in SCA3-related neuropathy.
Why This Matters
Peripheral neuropathy is the most common inherited neurological disorder worldwide, yet there are currently no preventative treatments. By pinpointing sensory neurons as major drivers of symptoms in SCA3, this research opens new therapeutic avenues. Approaches that dampen toxic activity in these cells could ease pain and mobility issues, improving quality of life for patients.
The study also reinforces a broader lesson: neurodegenerative diseases like SCA3 can affect not just the brain, but the entire nervous system. Understanding the full scope of a disease’s impact on the nervous system is essential for designing holistic treatments.
Looking Forward
While these findings are based in mice, the parallels to human SCA3 are strong. Both patients and the KI mice show abnormal protein buildup in sensory neurons, loss of peripheral nerve fibers, and impaired nerve conduction. Future research could explore whether therapies such as mutant ATXN3 silencing or cell-specific delivery systems can be tailored to target sensory neurons in humans.
Our study shows that even in complex, multisystemic disorders like SCA3, tackling the right cell type can make a measurable difference. By shifting some of the spotlight from the brain to the peripheral nervous system, we hope to uncover new strategies that could one day bring relief to thousands of people living with inherited neuropathies.
misciwriters.com 