Multiple sclerosis: hunting for new RNA markers in blood

ILLU_0229_GG_Multiple Sclerosis

Multiple sclerosis (MS), a rare and chronic central nervous system disorder resulting from autoimmunity, occasionally steps into the public eye when it strikes a well-known person (such as in 1999, when talk show host Montel Williams revealed his diagnosis). In neuroscience and immunology laboratories, however, the disease is always a major topic of investigation. Researchers seek to find not only what drives its progression, but also what markers might help clinicians find it early, and a new study offers fresh potential biomarkers in the form of long noncoding RNAs (lncRNA). Before I get into the study, let’s talk briefly about what we already know about MS.

Nerves are protected and insulated by a substance called myelin. It’s mostly made up of lipids, including cholesterol, along with water and protein, and is produced by Schwann cells in the peripheral nervous system, and oligodendrocytes in the central nervous system. Surrounding a nerve’s axons, myelin acts similarly to an insulator around any electrical wire, preventing loss of the current and helping to speed up the transmission of signals.

In MS, the immune system attacks and destroys myelin in the brain and spinal cord, which impairs normal communication in the nervous system. It’s not yet clear what triggers the autoimmune response, but it’s characterized by inflammation and areas of scar tissue called plaques, as well as eventual axon damage. Sufferers experience a breakdown in vision and muscle strength and coordination, but progression is variable; most MS patients begin with what’s called “relapsing-remitting” MS (RR-MS), where symptoms appear and then go into remission for an unpredictable period of time, sometimes leaving no lasting damage. However, a majority of these patients, if their RR-MS is severe and untreated, will go into secondary progressive MS eventually (1).

Because of the unpredictable nature of MS, biomarkers for diagnosis, prognosis and treatment efficacy are a major topic of interest in current research. One especially intriguing avenue is the potential of noncoding RNAs. microRNAs and lncRNAs are present in the circulation, so they can be analyzed relatively non-invasively, and research has already identified possible candidates for noncoding RNA biomarkers in Alzheimer’s disease and other neurological conditions (download the webinar for more information). For example, miR-34b has been suggested as a potential biomarker for Huntington’s disease, given its upregulation in plasma prior to the onset of symptoms, and miR-146 can be detected in blood monocytes during early Alzheimer’s disease (2). With regard to lncRNAs, BACE1-AS is upregulated in Alzheimer’s disease. This lncRNA increases the stability of the BACE1 mRNA, whose protein is known to be involved in beta-amyloid plaque formation (3). BC200 is another lncRNA that has been linked to Alzheimer’s disease (4).

Taking into account the role of inflammation in MS and the previous associations of lncRNA with neurodegeneration and inflammation, could there be lncRNAs that would serve as MS biomarkers? A recent study by Santoro et al. tackles this question. The team screened serum from patients with RR-MS, controls and patients with idiopathic inflammatory myopathy (IIM), enabling comparison with another inflammatory process (5).

Using the RT2 lncRNA PCR Array for Human Inflammatory Response & Autoimmunity, they searched for lncRNAs that were significantly upregulated in RR-MS patients compared to controls, identifying 3 – NEAT1, TUG1 and RN7SK RNA. Pairing NEAT1 with LRRC75A antisense RNA1 for relative expression yielded a 3.1-fold upregulation of NEAT1 between the RR-MS group and the control group. Only RN7SK was also upregulated in IIM patients, and 3 other lncRNAs were also significantly upregulated in IIM, including LINC00324, SDCBP2-AS1 and SNORA73A (5).

What is the significance of each of these lncRNAs? NEAT1 stands for nuclear paraspeckle assembly transcript 1, and as the name implies, it’s involved in paraspeckle assembly. This function appears to be important in TLR3 signaling, where NEAT1 promotes IL-8 expression by removing a repressive paraspeckle protein from its promoter. The authors note that increased IL-8 has been observed in RR-MS serum, as well as in MS brains. TUG1 (taurine upregulated 1) is a downstream target of p53 that is upregulated in Huntingdon’s disease, suggesting that it may be involved in apoptosis during neurodegeneration. Finally, RN7SK RNA (7SK small nuclear RNA) represses part of the P-TEFb cellular kinase complex, which is involved in CD4+ T cell differentiation. This could influence the inflammatory component of not only MS, but also IIM, both of which showed upregulation of RN7SK (5).

As with any promising preliminary biomarker study, a lot of work still lies ahead. Identifying potential biomarkers is just the first step in figuring out whether they’ll be useful in the clinic. Testing in a larger cohort often follows, which includes statistics on the ability of the markers (or a combination of them) to predict and distinguish disease. Small-scale translational studies like this one are an important milestone in presenting candidates to proceed down that funnel, and technology is continually progressing to expand our ability to find altered expression of RNAs and verify them prior to using larger populations. Targeted qPCR arrays for RNAs like the one used here, or customized arrays that can verify a unique RNA list gleaned from RNA sequencing studies, are a terrific starting place. If you’d like to learn more, download our webinar on noncoding RNAs in neurodegenerative diseases!

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References:

  1. 1. Multiple Sclerosis: Hope Through Research. National Institute of Neurological Disorders and Stroke. Last modified November 19, 2015. Accessed May 2, 2016. Link
  2. 2. Rege, S.D. et al. (2013) Noncoding RNAs in neurodegenerative diseases. ISRN Neurology 2013, 375852. Link
  3. 3. Sanchez, Y. and Huarte, M. (2013) Long non-coding RNAs: challenges for diagnosis and therapies. Nucleic Acid Ther. 23, 15. Link
  4. 4. Sosinska, P. et al. (2015) The double-edged sword of long non-coding RNA: the role of human brain-specific BC200 RNA in translational control, neurodegenerative diseases, and cancer. Mutat. Res. Rev. Mutat. Res. 766, 58. Link
  5. 5. Santoro, M. et al. (2016) Expression profile of long non-coding RNAs in serum of patients with multiple sclerosis. J. Mol. Neurosci. 59, 18. Link
Ali Bierly

Ali Bierly, PhD is a Global Market Manager in Translational Sciences at QIAGEN, and has written on a number of scientific topics in the biotech industry as the author of QIAGEN's Reviews Online. She received her PhD from Cornell University in 2009, studying the immune response to a protozoan parasite, Toxoplasma gondii. Ali has a keen interest in the emerging importance of microRNA and other circulating nucleic acids as biomarkers for disease.

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