NYSCF Collaboration Finds Possible Mechanism Behind Tired Brain Cells in Progressive MS


The Context: In multiple sclerosis (MS), brain cells degenerate and malfunction, leaving patients with symptoms such as numbness, weakness, vision loss, tremor, fatigue, and cognitive impairment. Progressive MS is a severe form of the disease in which these symptoms persistently worsen without periods of remission. The reason for brain cell dysfunction in MS remains unknown, but one source is hypothesized to be deficiencies in the function of mitochondria, the energy powerhouses of the cell.

The Study: Researchers from the City University of New York (CUNY) and the Icahn School of Medicine at Mount Sinai in collaboration with The NYSCF Research Institute’s Dr. Valentina Fossati examined how CSF (a fluid found in the brain and spinal cord that bathes the cells in our central nervous system) taken from MS patients affected the function of rat brain cells. The team found that brain cells exposed to the CSF of progressive MS patients had impaired mitochondrial activity, an indicator that the cells might not be able to produce enough energy to sustain themselves, leading to their eventual degeneration.

The Importance: This study suggests that certain lipids (fats) found in the CSF may be harmful to brain cells in MS patients by impairing their mitochondrial energy metabolism, which may be a worthwhile target for the development of new MS therapies.

The most severe form of MS is progressive MS, in which patients’ symptoms immediately and continuously worsen rather than coming and going as they would in relapsing/remitting MS. Progressive MS does not respond well to current therapies, leaving patients in desperate need of better treatment options.

We know that MS of all types is a result of neurodegeneration, but what exactly causes the degeneration is unknown. Recent research has suggested that dysfunctional mitochondria (the structures that give our cells energy) may play a role in this process, but what exactly causes the mitochondria to become weak and ineffective is not well understood.

A new study published in Brain by researchers at the City University of New York (CUNY) and the Icahn School of Medicine at Mount Sinai in collaboration with NYSCF Research Institute Senior Principal Investigator Valentina Fossati, PhD, identifies a possible source of mitochondrial dysfunction: the fluid that bathes your brain cells.

This fluid, called cerebrospinal fluid (or “CSF”) contains a myriad of substances that replenish cells and help them stay healthy. In neurological diseases, however, its composition can be perturbed, with adverse effects on the cells it surrounds.

“Because the brain is bathed by the CSF, we asked whether treating cultured neurons with the CSF from MS patients with a relapsing/remitting or a progressive disease course would possibly elicit different effects on neuronal mitochondrial function,” said the study’s primary investigator Patrizia Casaccia, PhD, Einstein Professor of Biology at The Graduate Center and founding director of the Neuroscience Initiative at the ASRC in a press release from CUNY.

In the study, the team extracted CSF from patients with both forms of MS as well as healthy controls and then exposed rat brain cells to the samples. They found that the brain cells exposed to CSF from progressive MS patients showed elongated mitochondria with impaired activity.

When the team analyzed the contents of the CSF samples, they found that a certain lipid, or fat molecule type, within the CSF of progressive MS patients called “ceramides” might be behind the dysfunction. To test how ceramides affect mitochondrial function, the researchers put rat brain cells in a medium (or “cell food”) rich with ceramides and found that the cells increased their uptake of glucose—a sugar cells need to sustain energy. This suggests that the ceramides impaired the mitochondria’s ability to metabolize and use glucose, requiring it to extract more of the sugar from the medium than normal.

Together, these findings suggest that the CSF could affect mitochondrial function in progressive MS and deplete cells of their energy (possibly through an abundance of ceramides). Future treatments may be able to target this mechanism to help cells maintain their energy and keep them from degenerating, in turn addressing a key issue in progressive MS and hopefully bringing relief to patients.

Learn more about NYSCF’s MS program here.

Journal Article:

A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis
Maureen Wentling, Carlos Lopez-Gomez, Hye-Jin Park, Mario Amatruda, Achilles Ntranos, James Aramini, Maria Petracca, Tom Rusielewicz, Emily Chen, Vladimir Tolstikov, Michael Kiebish, Valentina Fossati, Matilde Inglese Catarina, M Quinzii, Ilana Katz Sand, Patrizia Casaccia.Brain. 2019. doi: https://doi.org/10.1093/brain/awz201

Image Credit: Jeremy Weichsel at Biovisioning

The top portion of this graphic features neurons (blue) with axons wrapped by normal myelin (yellow). The lower portion of this graphic illustrates neurons with pathological axons wrapped by damaged myelin (yellow and pink). The elongated mitochondria (purple) in the lower portion are dysfunctional and characterized by accumulation of toxic ceramides (green).

Diseases & Conditions:

Multiple Sclerosis

People mentioned: