Multiple sclerosis (MS) is an inflammatory disease in which the immune system attacks the central nervous system.
The molecular mechanisms at the origin of this disease remain poorly understood. In an article published in Life Science Alliancescientists reveal how loss of control of theenzyme that reads genes can explain several aspects of disease.
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Multiple Sclerosis, an autoimmune disease still poorly understood
Multiple Sclerosis (MS) is a chronic autoimmune disease of the nervous system central, characterized by a progressive degradation of myelin, a substance which envelops and protects the fibers nervous. This demyelination disrupts the transmission of nerve signals between the brainthe spinal cord and the rest of the body, causing many neurological symptoms. In terms of mechanisms, MS is mainly marked by an abnormal immune response where T lymphocytes attack myelin as if it were a foreign body.
The origins of this autoimmune response remain poorly understood. Research suggests a complex mix of genetic, environmental and infectious factors, but no single molecular mechanism has been identified as the direct cause.
A new molecular mechanism revealed
By analyzing rare RNAs, the study shows that, in certain MS patients, deregulation of the expression genetic in immune cells responsible for the destruction of pathogens is linked to dysfunctions of the Integrator complex, a protein machinery essential for the maturation of non-coding RNAs.
Because of this dysfunction, the RNA produced at the level of DNA sequences regulating gene expression are longer and more abundant. However, these sequences, also called “enhancers”, come in part from ancient viruses, domesticated and used by the cell to better control genetic expression.
Thus, the imperfect maturation of enhancer RNAs could explain the production of viral genes frequently observed in MS patients.
But the Integrator complex also influences the activity of RNA polymerase II, the enzyme responsible for reading protein-coding genes. In the absence of optimal Integrator activity, RNA polymerase II initiates transcription more frequently, but struggles to complete it. This promotes the expression of short genes, such as those involved ininflammationwhile long genes, essential for example for the integrity of endothelia, are not entirely transcribed, thus compromising their expression.
Thus, several transcriptional observations in MS patients find their explanation in the same phenomenon, which greatly improves our understanding of this complex disease.
References:
Porozhan Y, Carstensen M, Thouroude S, et al. Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis.
Life Sci Alliance. 2024;7(10):e202402586. Published 2024 Jul 19.
doi:10.26508/lsa.202402586
