The cerebrospinal fluid (CSF) of people with progressive multiple sclerosis (MS) contains elevated levels of specific fatty molecules that disrupt the energy “powerhouses” of nerve cells, and appear to underlie the neurodegeneration seen on brain scans of these patients, a study reveals.
The research, which compared the CSF of relapsing-remitting (RRMS) and progressive MS patients, identified mechanisms that may support new treatments aiming to effectively halt progressive forms of the disease, its researchers say.
The study “A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis” was published in the journal Brain.
RRMS, the most common form of MS, is characterized by demyelinating inflammatory episodes with clinical symptoms, followed by periods of clinical remission. Approximately half of these patients later transition to secondary progressive MS (SPMS), with continuing neurological decline. Unlike RRMS, SPMS is marked by a gradual, but increasing, burden of neurological disability without clinical remission.
Effective therapies help in managing RRMS, but treatments for progressive MS are more challenging.
Prior research suggests that the cellular structures that work as energy powerhouses — called mitochondria — are not functioning properly in the brain of people with progressive MS. However, the chain of events at the molecular level that underlies this process is still unknown.
“Because the brain is bathed by the cerebrospinal fluid (CSF), we asked whether treating cultured neurons [nerve cells] with the CSF from MS patients with a relapsing-remitting or a progressive disease course would possibly elicit different effects on neuronal mitochondrial function,” Patrizia Casaccia, MD, PhD, the study’s senior leader, said in a press release.
The CSF is a clear, plasma-like fluid found in the central nervous system (CNS), composed of the brain and spinal cord. There, it plays several important roles: it provides the CNS with nutrients (glucose or sugar, proteins and fats), helps to remove its waste products, contributes to immune system defenses, and absorbs shocks.
Researchers exposed rat neurons growing in the lab (cultured cells) to CSF samples collected from multiple MS patients, including 15 people with RRMS and 29 with progressive MS (15 with SPMS, and 14 with primary progressive MS or PPMS), to investigate potential mechanisms of neurodegeneration.
Visualizing neurons under a microscope revealed “dramatic differences” in the mitochondria of nerve cells exposed to the CSF of progressive MS patients, they said. Such exposure disturbed the mitochondria’s shape, making them fuse and elongate. Further analysis showed these changes rendered mitochondria less able to produce energy, eventually resulting in nerve cell damage.
To find out which molecular changes might underlie those neurotoxic effects, and after excluding the involvement of proteins, the scientists screened for changes in the abundance of multiple lipids (fats) in the CSF of RRMS and progressive MS patients.
Progressive patients had higher CSF levels of a specific ceramide (C24), a family of waxy lipid molecules abundant in the membrane of cells, the screening revealed.
Supporting ceramide-driven neurotoxicity, rat neurons exposed to C24 showed mitochondria impairments and neuronal damage akin to those neurons put in contact with CSF from progressive MS patients.
The scientists further discovered that ceramide’s harmful effects depended on two cellular mechanisms. “On one end, ceramides impaired the ability of neurons to make energy by directly damaging the mitochondria. On the other end, they also forced neurons to more rapidly uptake glucose in an attempt to provide energy for the cell,” said Maureen Wentling, a research associate in the Casaccia lab, and the study’s first author.
Consistent with this, adding glucose to the cultured rat neurons rescued the neurotoxic effect of the CSF.
“Thus, ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration, but also decreased the bioavailability of glucose by increasing its uptake,” the researchers wrote.
“Together these data suggest a condition of ‘virtual hypoglycosis’ [low glucose levels] induced by the CSF of progressive patients in cultured neurons, and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients,” they concluded.