Suppressed RNA-polymerase 1 pathway is associated with benign multiple sclerosis.
Benign multiple sclerosis (BMS) occurs in about 15% of patients with relapsing-remitting multiple sclerosis (RRMS) that over time do not develop significant neurological disability. The molecular events associated with BMS are not clearly understood. This study sought to underlie the biological mechanisms associated with BMS. Blood samples obtained from a cohort of 31 patients with BMS and 36 patients with RRMS were applied for gene expression microarray analysis using HG-U133A-2 array (Affymetrix). Data were analyzed by Partek and pathway reconstruction was performed by Ingenuity for the most informative genes (MIGs). We identified a differing gene expression signature of 406 MIGs between BMS patients, mean±SE age 44.5±1.5 years, 24 females, 7 males, EDSS 1.9±0.2, disease duration 17.0±1.3 years, and RRMS patients, age 40.3±1.8 years, 24 females, 12 males, EDSS 3.5±0.2, disease duration 10.9±1.4 years. The signature was enriched by genes related RNA polymerase I (POL-1) transcription, general inflammatory response and activation of cell death. The most significant under-expressed pathway operating in BMS was the POL-1 pathway (p = 4.0*10(-5)) known while suppressed to activate P53 dependent apoptosis and to suppress NFκB induced inflammation. In accordance, of the 30 P53 target genes presented within the BMS signature, 19 had expression direction consistent with P53 activation. The transcripts within the pathway include POL-1 transcription factor 3 (RRN3, p = 4.8*10(-5)), POL-1 polypeptide D (POLR1D, p = 2.2*10(-4)), leucine-rich PPR-motif containing protein (LRPPRC p = 2.3*10(-5)), followed by suppression of the downstream family of ribosomal genes like RPL3, 6,13,22 and RPS6. In accordance POL-1 transcript and release factor PTRF that terminates POL-1 transcription, was over-expressed (p = 4.4*10(-3)). Verification of POL-1 pathway key genes was confirmed by qRT-PCR, and RRN3 silencing resulted in significant increase in the apoptosis level of PBMC sub-populations in RRMS patients. Our findings demonstrate that suppression of POL-1 pathway induce the low disease activity of BMS.
Multiple Sclerosis Center, Neurogenomics Laboratory, Sheba Medical Center, Tel-Hashomer and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel. Anat.Achiron@sheba.health.gov.il
Anat
A
Achiron
Anna
A
Feldman
David
D
Magalashvili
Mark
M
Dolev
Michael
M
Gurevich
D000328:Adult; D017209:Apoptosis; D015331:Cohort Studies; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics; D012318:RNA Polymerase I / Q000235:genetics* / Q000378:metabolism; D000090822:Ribosomal Protein L3; D015398:Signal Transduction
D035463:Pol1 Transcription Initiation Complex Proteins; C000716547:RPL3 protein, human; C428423:RRN3 protein, human; D000090822:Ribosomal Protein L3; D012318:RNA Polymerase I