Cell-free Mitochondrial DNA in Cerebrospinal Fluid of Progressive MS Patients May Point to Neurodegeneration

Cell-free Mitochondrial DNA in Cerebrospinal Fluid of Progressive MS Patients May Point to Neurodegeneration

Cerebrospinal fluid of progressive multiple sclerosis (MS) patients may carry lower levels of cell-free mitochondrial DNA, according to a team of researchers who say this may be a sign of neurodegeneration among these patients.

The study “Cell-free mitochondrial DNA in progressive multiple sclerosis” was published in the journal Mitochondrion.

Poor function of mitochondria — the cells’ energy powerhouses — has been linked to MS, with patients showing alterations in mitochondria architecture, gene expression, and metabolic activity.

Moreover, certain mitochondrial genetic variants are associated with MS. For example, patients with the mitochondria haplogroup J variants (a cluster of genes with certain variations) were reported to have a 1.5 higher risk for developing primary progressive MS, while other variants (namely the haplogroup K) decrease this risk.

Recently, researchers identified increased levels of cell-free mitochondrial DNA in the cerebrospinal fluid (the liquid around the brain and spinal cord) in both relapsing-remitting MS (RRMS) and progressive MS patients, with high levels correlating with brain shrinkage (atrophy).

Since currently there is a lack of accurate predictors of neurodegeneration in MS, a team of researchers evaluated the role of circulating cell-free mitochondrial DNA in MS progression.

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They quantified cell-free mitochondrial DNA abundance and integrity in cerebrospinal fluid collected from post-mortem brains of 36 patients with end-stage progressive MS, in whom neurodegeneration is evident. Researchers performed the same analysis in samples from 43 matched healthy controls.

In its analysis, the team looked at how the levels of cell-free mitochondrial DNA correlated with known markers of neurodegeneration and progressive MS.

The post-mortem progressive MS cases showed a significant reduction in cell-free mitochondrial DNA levels compared to controls, a result in clear contrast to what was previously observed — that the levels of mitochondrial DNA were increased in MS patients.

Nonetheless, these results are in line with what was found for Parkinson’s and Alzheimer’s disease, in which cell-free mitochondrial DNA was associated with neurodegeneration.

These findings support “our hypothesis that ccf-mtDNA [cell-free mitochondrial DNA] may be a component of neurodegeneration,” researchers wrote.

The cell-free mitochondrial DNA detected in progressive MS patients was, in the majority of the cases, intact (the integrity was evaluated by the number of deletions) and similar to that of matched controls — deletions of 10 percent or higher in the DNA were detected in 13 percent of progressive MS cases and in 20 percent of the controls.

Although the frequency of mutations was higher in MS cases compared to controls, the differences were not statistically significant.

With the exception of the neurodegeneration marker protein called S100 calcium binding protein B, the other markers of neurodegeneration and of progressive MS analyzed showed no differences between controls and MS patients.

The same was observed for the chitinase 3 like 1 (CHI3L1) protein, used to differentiate active and inactive progressive MS, and chitinase 3 like 2 (CHI3L2), used to differentiate progressive MS from RRMS.

Also, researchers found no correlation between protein markers of neurodegeneration and the levels and integrity of cell-free mitochondrial DNA.

Overall, the results are contrary to previous findings and suggest that lower levels of cell-free mitochondrial DNA may indicate neurodegeneration in progressive MS.

“Our findings support our hypothesis that decreased ccf-mtDNA may be an indicator of neurodegeneration in PMS [progressive MS]. Although we observed a significant association, we urge caution” the researchers wrote, “we cannot exclude the possibility that ccf-mtDNA levels rise in-life in response to the onset of disease and then reduce as neurodegeneration increases.”

“Therefore, whilst reduced ccf-mtDNA may be a hallmark of the presence of neurodegeneration, it is not particularly useful as a biomarker,” the team concluded, adding more studies are needed to better understand the link between cell-free mitochondrial DNA and neurodegeneration in progressive MS.

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