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Published on: December 9, 2015
Polymerase-1 pathway activation in acute multiple sclerosis relapse
Anat Achiron1, Rina Zilkha-Falb1, Anna Feldman1
1Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel.
Background:
Increased expression of RNA polymerase 1 (POL1) molecular pathway was reported to be associated with increased disease activity in patients with multiple sclerosis (MS). However, the operating molecular mechanisms that characterize the pattern of acute MS relapse activity has not been thoroughly studied.
Objective:
To assess POL1 pathway expression during acute MS relapse.
Methods:
We studied POL1 pathway associated biomarkers during the first acute optic neuritis attack of MS, and in relapsing-remitting MS patients treated with disease-modifying drugs (DMDs) experiencing an acute MS relapse or a radiological relapse using gene expression microarrays and quantitative RT-PCR.
Results:
In MS patients (N = 6) during the first acute optic neuritis attack POL1 pathway activation was evident by over-expression of POL1 related network including transcription factor UBTF and downstream components of Assembly of RNA POL1 complex (p=1.92E-03). POL1 related biomarkers RRN3, POLR1D and LRPPRC were over-expressed x1.6 (p = .002), ×1.7 (p = .01) and x2.0 (p = .001) times higher respectively, in MS patients (N = 30) during acute clinical relapse as compared with remission. Similarly, in MS patients (N = 21) that presented with a radiological relapse, we observed significant activation of POL1 related biomarkers including RRN3 (p = .01), POLR1D (p = .002), POLR1E (p = .0001) and LRPPRC (p = .006), as compared with remission, as well as overexpression of a large group of genes encoding ribosomal proteins like RPS6KA3 (p = 7.2E-6), RRP8 (p = .0002) and RPCS9 (p = .0008).
Conclusions:
Our findings demonstrated increased POL1 pathway activity in acute MS relapse and suggest that targeted inactivation of POL1 pathway represent a novel strategy for a better treatment of acute MS relapse.
Insights
Increased RNA polymerase 1 (POL1) pathway activity is evident during acute multiple sclerosis (MS) relapses. Targeting this pathway may offer a new therapeutic strategy for managing MS relapses.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Genetics
Background:
- Increased RNA polymerase 1 (POL1) pathway expression correlates with multiple sclerosis (MS) disease activity.
- The precise molecular mechanisms driving acute MS relapse remain incompletely understood.
Purpose of the Study:
- To investigate the expression of the POL1 pathway during acute MS relapses.
- To identify key POL1-associated biomarkers indicative of MS relapse activity.
Main Methods:
- Gene expression microarrays and quantitative RT-PCR were employed.
- Analysis included patients experiencing their first acute optic neuritis attack, and relapsing-remitting MS patients during clinical or radiological relapse.
- Biomarker expression was compared between relapse and remission states.
Main Results:
- POL1 pathway activation was observed during the first acute optic neuritis attack in MS patients.
- Biomarkers such as RRN3, POL1D, and LRPPRC were significantly overexpressed during acute clinical relapses compared to remission.
- Radiological relapses also showed significant activation of POL1-related biomarkers and overexpression of ribosomal protein genes.
Conclusions:
- The study demonstrates heightened POL1 pathway activity during acute MS relapses.
- Targeting the POL1 pathway presents a potential novel therapeutic strategy for improving acute MS relapse treatment.
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