Summary: A new study identifies mitochondrial dysfunction as a central factor in the loss of Purkinje neurons in the cerebellum, a process that contributes to motor impairment in people with multiple sclerosis (MS). Inflammation and demyelination in the cerebellum disrupt mitochondrial function—the cell’s energy system—leading to energy failure, neuronal damage, and ataxia.
The researchers combined analysis of human postmortem cerebellar tissue with experiments in an MS-like mouse model and found that reduced levels of mitochondrial proteins coincided with Purkinje cell degeneration. These results indicate that preserving mitochondrial health could slow cerebellar degeneration and help maintain coordination and balance in MS.
Key Facts:
- Energy breakdown: Damage to mitochondria in Purkinje neurons undermines cellular function and contributes to cell death.
- Motor control at risk: Loss of Purkinje cells in the cerebellum drives coordination problems and ataxia in MS.
- Therapeutic potential: Intervening to support mitochondrial function may slow MS-related neurological decline.
Source: UCR
Multiple sclerosis (MS) affects an estimated 2.3 million people worldwide.
Roughly 80% of people with MS show inflammation in the cerebellum, the brain region responsible for movement coordination and balance. Cerebellar inflammation and demyelination can cause tremors, impaired coordination, and other motor-control problems that often worsen over time as healthy brain tissue is lost.
A University of California, Riverside study published in the Proceedings of the National Academy of Sciences examined why the cerebellum degenerates in MS. The investigators propose that mitochondrial dysfunction links inflammation and demyelination to the progressive loss of a specific class of neurons known as Purkinje cells, which are essential for smooth, coordinated movement.
MS is characterized by chronic inflammation and the loss of myelin, the insulating layer that surrounds nerve fibers. When myelin is damaged, electrical signaling along neurons becomes inefficient. Mitochondria, the organelles that generate most of the cell’s energy, are particularly vulnerable to these disease processes, and their failure can accelerate neuronal injury.
“Our study, led by graduate student Kelley Atkinson, shows that inflammation and demyelination in the cerebellum impair mitochondrial function and contribute to Purkinje cell loss,” said Seema Tiwari-Woodruff, professor of biomedical sciences at UC Riverside School of Medicine and senior author of the paper. “We observed a marked decrease in the mitochondrial protein COXIV in demyelinated Purkinje cells, which points to mitochondrial dysfunction as a direct contributor to cell death and cerebellar damage.”
Purkinje cells
The cerebellum integrates information from muscles, the vestibular system, and sensory inputs to regulate posture, balance, and precise movement. Purkinje neurons are large, highly active cells in the cerebellum that coordinate timing and smooth execution of voluntary actions—from walking to fine motor tasks.
“Because Purkinje cells are so crucial for coordination, their degeneration produces ataxia and serious mobility impairments,” Tiwari-Woodruff explained. The team’s analysis of human MS cerebellar tissue revealed fewer dendritic branches, extensive myelin loss, and evidence of mitochondrial dysfunction in these neurons—signs that their energy supply is failing.
Powering down
To model disease progression, the researchers used experimental autoimmune encephalomyelitis (EAE), a widely used mouse model that reproduces many features of MS. EAE mice showed progressive Purkinje cell loss similar to human samples, and surviving neurons exhibited impaired mitochondrial function.
“We found that mitochondrial failure and early myelin breakdown precede the frank loss of Purkinje cells,” Tiwari-Woodruff said. “Reduced cellular energy, combined with demyelination, appears to set the stage for later neuronal death as disease severity increases.” Although no model captures all aspects of MS, these parallel findings across human tissue and EAE mice strengthen the link between mitochondrial health and cerebellar degeneration.
The authors suggest that therapies aimed at supporting mitochondrial function—improving cellular energy production, protecting mitochondria from inflammatory damage, or promoting myelin repair—could help preserve motor function and slow neurological decline in people with MS.
Fueling the future
Next steps for the group include examining whether mitochondrial impairment extends beyond Purkinje cells to other cerebellar cell types such as oligodendrocytes, which produce myelin, and astrocytes, which maintain neuronal health. Ongoing projects are focused on assessing mitochondria in specific cerebellar cell populations to identify early intervention strategies.
“Understanding how mitochondrial dysfunction intersects with immune-driven damage and myelin loss could reveal ways to protect the cerebellum before irreversible degeneration occurs,” Tiwari-Woodruff said. “That could mean boosting energy metabolism in vulnerable cells, enhancing remyelination, or tempering immune activity to limit damage—approaches that may preserve balance and coordination for people with MS.”
Tiwari-Woodruff noted the importance of continued investment in basic and translational research. “Reducing funding for science slows progress when it is most needed. Public support for research is essential to advance therapies that improve lives.”
The study team included Kelley Atkinson, Shane Desfor, Micah Feria, Maria T. Sekyia, Marvellous Osunde, Sandhya Sriram, Saima Nooria, Wendy Rincóna, and Britany Belloa. The researchers analyzed postmortem cerebellar tissue from people with secondary progressive MS and control samples obtained from the NIH NeuroBioBank and the Cleveland Clinic.
Funding: The research was supported by a grant from the National Multiple Sclerosis Society.
About this multiple sclerosis research news
Author: Iqbal Pittalwala
Source: UCR
Contact: Iqbal Pittalwala – UCR
Image: The image is credited to Neuroscience News
Original Research: The findings will appear in PNAS