Researchers at the University of California, Riverside, have identified how inflammation in multiple sclerosis disrupts mitochondrial function in the brain, leading to the loss of key neurons that control balance and coordination. Published in the Proceedings of the National Academy of Sciences, the findings highlight a potential pathway for new treatments to preserve mobility in the 2.3 million people affected by the disease worldwide. The study examined human brain tissue and a mouse model to trace these energy failures over time.
Multiple sclerosis (MS) impacts around 2.3 million individuals globally, with about 80% experiencing inflammation in the cerebellum, the brain region responsible for balance and coordinated movement. This damage often results in tremors, unsteady gait, and muscle control difficulties that worsen progressively as cerebellar tissue deteriorates.
A new investigation from the University of California, Riverside, led by biomedical sciences professor Seema Tiwari-Woodruff, reveals that malfunctioning mitochondria— the cell's energy producers—play a central role in this decline. The research, conducted by graduate student Kelley Atkinson and colleagues, focused on Purkinje cells, specialized neurons in the cerebellum that enable precise actions like walking or reaching. "Inside the cerebellum are special cells called Purkinje neurons," Tiwari-Woodruff explained. "These large, highly active cells help coordinate smooth, precise movements—they're essential for balance and fine motor skills."
Analysis of postmortem cerebellar tissue from patients with secondary progressive MS, sourced from the National Institutes of Health's NeuroBioBank and the Cleveland Clinic, showed these neurons with reduced branches, demyelination (loss of the protective myelin sheath), and depleted levels of the mitochondrial protein COXIV. This energy shortfall appears to drive cell death and exacerbate ataxia, a hallmark of poor coordination.
To track the progression, the team used an experimental autoimmune encephalomyelitis (EAE) mouse model mimicking MS symptoms. Observations indicated early myelin breakdown and mitochondrial impairment, followed by later Purkinje cell loss. "The remaining neurons don't work as well because their mitochondria... start to fail," Tiwari-Woodruff noted. "We also saw that the myelin breaks down early in the disease. These problems—less energy, loss of myelin, and damaged neurons—start early, but the actual death of the brain cells tends to happen later."
Funded by the National Multiple Sclerosis Society, the study suggests targeting mitochondrial health could slow neurological decline. Future work will examine mitochondrial effects on other cerebellar cells, such as oligodendrocytes and astrocytes, potentially leading to therapies that boost energy supply, repair myelin, or modulate immunity early in the disease course. Tiwari-Woodruff emphasized the need for ongoing research investment: "Cutting funding to science only slows progress when we need it most."
The paper, titled "Decreased mitochondrial activity in the demyelinating cerebellum of progressive multiple sclerosis and chronic EAE contributes to Purkinje cell loss," was published in 2025.
