Summary: A research team at the University of Saskatchewan led by Dr. Michael Levin finds a link between a factor called ‘RNA binding protein heterogeneous nuclear ribonucleoprotein A1’ (hnRNP A1) and the slow and progressive loss of nerve fibres in multiple sclerosis (MS), also known as neurodegeneration. Understanding the mechanisms of neurodegeneration will support the next generation of MS therapeutics.
Background: DNA contains an individual’s genetic code or instructions for making proteins in the body and is contained in the cell nucleus. RNA acts as a key messenger carrying instructions from DNA in the nucleus to the cytoplasm, the fluid part of the cell, to make the body’s proteins. RNA is controlled by many factors including specialized proteins called ‘RNA binding proteins’. Defects in RNA binding proteins have been linked to neurodegeneration in several neurological diseases like ALS, dementia, and Huntington’s disease, but this link has not been shown in MS.
Details: The research team previously showed that the RNA binding protein, ‘heterogeneous nuclear ribonucleoprotein AI’ or hnRNP A1, is dysfunctional in MS. This study aimed to understand whether hnRNP A1 has a role in neurodegeneration in MS, as seen in other neurological diseases, using human and animal models.
Results:
- In the brains of people with progressive MS, the majority of hnRNP A1 was found in the cytoplasm (the fluid part of the cell) instead of the nucleus as seen in healthy people. This dysregulation caused changes in the types of RNA needed for nerve cell maintenance and survival.
- In animal models of severe MS, hnRNP A1 was found to bind less to RNA compared to those with mild MS. This dysfunction prevented the cell from controlling key RNA processes that can impact neurodegeneration.
- In human MS brains, hnRNP A1 dysfunction disrupted important cellular processes in nerve cells to promote neurodegeneration.
- Based on these findings, hnRNP A1 dysfunction affects a number of RNAs and these changes may be accumulating over months and years to affect the health of nerve cells, thereby leading to neurodegeneration.
Impact: This is the first study to show the role for an RNA binding protein in contributing to neurodegeneration in MS. A better understanding of the factors and mechanisms that drive neurodegeneration will support the development of future therapies to halt disease progression and permanent disability in MS.
Reference:
Hannah E. Salapa, Patricia A. Thibault,, Cole D. Libner, Yulian Ding, Joseph-Patrick W. E. Clarke, Connor Denomy , Catherine Hutchinson, Hashim M. Abidullah, S. Austin Hammond , Landon Pastushok , Frederick S. Vizeacoumar & Michael C. Levin (2024), hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS). Nature Communications Link to article – here.
Additional Information: