Mitochondrial dysfunction drives cerebellar damage in multiple sclerosis

Multiple sclerosis (MS) affects an estimated 2.3 million people worldwide. Approximately 80% of people with MS have inflammation in the cerebellum, the part of the brain that helps control movement and balance, potentially leading to tremors, poor coordination, and trouble with motor control. These problems often persist and can worsen over time, as the cerebellum gradually loses healthy brain tissue.

A University of California, Riverside study, published today in the Proceedings of the National Academy of Sciences, now sheds light on the underlying mechanisms of cerebellar degeneration in MS, suggesting that mitochondrial dysfunction may play a key role in the progressive loss of neuronal cells called Purkinje cells and worsening motor impairments.

MS is marked by chronic inflammation and demyelination in the central nervous system. Demyelination is the process in which the myelin sheath - a protective, insulating layer surrounding nerve fibers in the brain and spinal cord - is damaged or lost. This disruption interferes with the normal transmission of electrical signals along the nerves, resulting in various neurological issues. Mitochondria are vital structures within cells that generate most of the cell's energy, earning them the nickname "powerhouses" of the cell.

"Our study, conducted by my graduate student Kelley Atkinson, proposes that inflammation and demyelination in the cerebellum disrupt mitochondrial function, contributing to nerve damage and Purkinje cell loss," said Seema Tiwari-Woodruff, a professor of biomedical sciences in the UC Riverside School of Medicine, who led the research team. "We observed a significant loss of the mitochondrial protein COXIV in demyelinated Purkinje cells, suggesting that mitochondrial impairment contributes directly to cell death and cerebellar damage."

Purkinje cells

When we walk or move, many parts of our brain and body work together - our muscles, spine, eyes, ears, and especially our brain. A key brain area for movement and balance is the cerebellum.

Inside the cerebellum are special cells called Purkinje neurons. These large, highly active cells help coordinate smooth, precise movements - like dancing, throwing a ball, or even just walking. They're essential for balance and fine motor skills."

Seema Tiwari-Woodruff, professor of biomedical sciences, UC Riverside School of Medicine

Tiwari-Woodruff explained that in diseases like MS, the cerebellum can be damaged, and Purkinje cells often begin to die. This leads to problems with coordination and movement, a condition known as ataxia.

"Our research looked at brain tissue from MS patients and found major issues in these neurons: they had fewer branches, were losing myelin, and had mitochondrial problems - meaning their energy supply was failing," Tiwari-Woodruff said. "Because Purkinje cells play such a central role in movement, their loss can cause serious mobility issues. Understanding why they're damaged in MS could help us find better treatments to protect movement and balance in people with the disease."

Powering down

The team also used a well-established mouse model known as experimental autoimmune encephalomyelitis (EAE) - a mouse model that develops MS-like symptoms - to investigate mitochondrial alterations during disease progression.

The researchers found that the EAE mice lost Purkinje cells over time, just like people with MS did.

"The remaining neurons don't work as well because their mitochondria, the energy-producing parts, start to fail," Tiwari-Woodruff said. "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, as the disease becomes more severe. The loss of energy in brain cells seems to be a key part of what causes damage in MS." 

Although the mouse model does not capture every aspect of MS, its similarities to human disease make it a valuable tool for studying neurodegeneration and testing potential therapies.

"Our findings offer critical insights into the progression of cerebellar dysfunction in MS," Tiwari-Woodruff said. "Targeting mitochondrial health may represent a promising strategy to slow or prevent neurological decline and improve quality of life for people living with MS. This research brings us a step closer to understanding the complex mechanisms of MS and developing more effective, targeted treatments for this debilitating disease."

Fueling the future

Next, the team will investigate whether the mitochondrial impairment found in Purkinje cells also affects other brain cells like oligodendrocytes, which help form white matter, or astrocytes, which support overall brain function.

"To answer this, one of our ongoing research projects is focused on studying mitochondria in specific types of brain cells in the cerebellum," Tiwari-Woodruff said. "Such research can open the door to finding ways to protect the brain early on - like boosting energy in brain cells, helping them repair their protective myelin coating, or calming the immune system before too much damage is done. This is especially important for people with MS who struggle with balance and coordination, as these symptoms are tied to damage in the cerebellum."

Tiwari-Woodruff emphasized that disease-related research is vital to improving lives.

"Cutting funding to science only slows progress when we need it most," she said. "Public support for research matters now more than ever."

Tiwari-Woodruff and Atkinson were joined in the study by Shane Desfor, Micah Feria, Maria T. Sekyia, Marvellous Osunde, Sandhya Sriram, Saima Nooria, Wendy Rincóna, and Britany Belloa.

The research team analyzed postmortem cerebellar tissue from patients with secondary progressive MS, alongside samples from healthy individuals, obtained from the National Institutes of Health's NeuroBioBank and the Cleveland Clinic.

The study was supported by a grant from the National Multiple Sclerosis Society.

The research paper is titled "Decreased mitochondrial activity in the demyelinating cerebellum of progressive multiple sclerosis and chronic EAE contributes to Purkinje cell loss."