Multiple sclerosis (MS) is a chronic inflammatory disorder that is thought to impact about 2.3 million people around the world. This disorder is characterized by the loss of a protective neuronal insulation called myelin in the central nervous system, and chronic inflammation. Many patients have inflammation in the cerebellum, an area that helps control movement; these individuals often have tremors and movement difficulties that tend to get worse over time. Eventually, MS patients may begin to lose healthy cerebellar tissue.
New research has suggested that in MS, the loss of myelin and inflammation in the cerebellum interferes with the function of cellular powerhouses known as mitochondria. This could be causing the death of neurons called Purkinje cells, making motor function worse and leading to a movement problem known as ataxia. The findings have been reported in the Proceedings of the National Academy of Sciences (PNAS).
In this study, the researchers analyzed cerebellar tissue in the post-mortem brains of secondary progressive MS patients, as well as unaffected individuals. This revealed neurons with serious problems in MS patients: they had less myelin, fewer branches, and mitochondrial issues. The neurons likely had less energy.
In demyelinated Purkinje cells, a protein expressed in mitochondria called COXIV was reduced. This suggests that mitochondrial dysfunction is a direct contributor to cell death and tissue damage, said senior study leader Seema Tiwari-Woodruff, a professor of biomedical sciences in the University of California, Riverside School of Medicine.
While the cerebellum is crucial to movement and balance, it also contains Purkinje neurons, which work to make movements "smooth and precise," noted Tiwari-Woodruff. "They’re essential for balance and fine motor skills.”
The study also utilized a mouse model that exhibits symptoms that are similar to those seen in MS. There was a progressive loss of Purkinje cells in these mice too.
“The remaining neurons don’t work as well because their mitochondria, the energy-producing parts, start to fail,” explained Tiwari-Woodruff. “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.”
This study has revealed “critical insights into the progression of cerebellar dysfunction in MS,” Tiwari-Woodruff said.
It may be possible to develop drugs that can improve mitochondrial health, which may help reduce or prevent the loss of neurons in MS, the researchers added.
The investigators are planning to continue this work to learn more about mitchondrial function in various cerebellar cells. The team also wants to explore various methods that could protect the brain, such as retaining myelin, reducing inflammation, or increasing cellular energy levels. To do that, reliable sources of funds are necessary.
“Cutting funding to science only slows progress when we need it most,” said Tiwari-Woodruff. “Public support for research matters now more than ever.”
Sources: UC Riverside, Proceedings of the National Academy of Sciences (PNAS)