Analysis Yields miRNA Linked With Atrophy in Patients With MS

Jared Kaltwasser

The new study identified altered microRNA (miRNA) in gray matter lesions, which could provide a new important marker of multiple sclerosis (MS) progression.

A new report has identified microRNA (miRNA) that are altered in the gray matter lesions (GMLs) of patients with progressive multiple sclerosis (MS) and which appear to correlate with cortical atrophy.

The findings, published in the Annals of Clinical and Translational Neurology, offer potential new markers of GML demyelination and targets for future therapies.

The authors noted that most of the existing literature regarding MS has focused on the demyelination of white matter (WM) regions of the central nervous system (CNS). However, the investigators said there is strong evidence that investigators need to look beyond WM.

“[M]any clinical characteristics like cognitive dysfunction and neurological disability have indicated cortical involvement associated with demyelination or secondary neurodegeneration,” they wrote. “In addition, early cortical involvement has been found to be associated with more rapid disease progression.”

Yet, although WM in CNS tissue can be easily detected using MRI, cortical brain regions are more difficult to identify with MRI, creating a pressing need to find other ways to track cortical MS pathology, they said.

The authors set out in hopes of identifying miRNA expression profiles in GMLs that correlated with atrophy measures in progressive MS, thereby opening the door to the use of cortical lesion biomarkers. To do so, they used global miRNA and gene expression profiling of GMLs, validating the results with real-time quantitative polymerase chain reaction, immuno-in situ hybridization, and immunohistochemistry.

Comparing gene expression profiles of myelinated areas of normal-appearing gray matter to those of demyelinated GMLs from patients with progressive MS, the investigators identified 82 miRNAs. Of those, 10 were significantly upregulated in GMLs and 17 were significantly downregulated.

Of the 82, 13 were also detected in serum samples and were associated with brain atrophy.

“The predicted target mRNAs of these miRNAs belonged to pathways associated with axonal guidance, TGF-β signaling, and FOXO signaling,” the investigators found. “Further, using state-of-the-art human protein–protein interactome network analysis, we mapped the 4 key GM atrophy-associated miRNAs (hsa-miR-149*, hsa-miR-20a, hsa-miR-29c, and hsa-miR-25) to their target mRNAs that were also changed in GMLs.”

The investigators said the target genes of the miRNAs that were associated with cortical atrophy were also associated with other factors, such as neuronal function, fatty acid synthesis, and inflammation.

“As we also correlated the expression of these miRNAs in serum, our results provide a method to study cortical changes in MS brains through peripheral monitoring,” they said.

While most existing research has focused on WM, the investigators said a previous report looking at miRNA expression from brain cortical lesions found higher numbers of upregulated and downregulated miRNAs, only 2 of which matched those identified in the new research (miR-1180 and miR-219-2-3p).

The investigators said the variance was likely due to the use of both different platforms and control tissue.

Additional research is warranted, the authors emphasized, to better understand the miRNAs and pathways and the mechanisms driving lesion formation and neuroprotection in progressive MS.

Reference

Tripathi A, Pandit I, Perles A, Zhou Y, Cheng F, Dutta R. Identifying miRNAs in multiple sclerosis gray matter lesions that correlate with atrophy measures. Ann Clin Transl Neurol. 2021;8(6):1279-1291. doi: 10.1002/acn3.51365