Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations
<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression...
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doaj-70ef3a996f3d41b793e956c4f3288e3e2020-11-25T00:13:41ZengBMCBMC Genomics1471-21642011-10-0112152710.1186/1471-2164-12-527Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutationsKocerha JannetKouri NaomiBaker MattFinch NiColeDeJesus-Hernandez MarielyGonzalez JohnChidamparam KumaravelJosephs Keith ABoeve Bradley FGraff-Radford Neill RCrook JuliaDickson Dennis WRademakers Rosa<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (<it>PGRN</it>) gene.</p> <p>Results</p> <p>Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying <it>PGRN </it>mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of <it>PGRN </it>mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.</p> <p>Conclusions</p> <p>Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by <it>PGRN </it>mutations and provides new insight into potential future therapeutic options.</p> http://www.biomedcentral.com/1471-2164/12/527Frontotemporal lobar degenerationTDP-43microRNAprogranulin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kocerha Jannet Kouri Naomi Baker Matt Finch NiCole DeJesus-Hernandez Mariely Gonzalez John Chidamparam Kumaravel Josephs Keith A Boeve Bradley F Graff-Radford Neill R Crook Julia Dickson Dennis W Rademakers Rosa |
spellingShingle |
Kocerha Jannet Kouri Naomi Baker Matt Finch NiCole DeJesus-Hernandez Mariely Gonzalez John Chidamparam Kumaravel Josephs Keith A Boeve Bradley F Graff-Radford Neill R Crook Julia Dickson Dennis W Rademakers Rosa Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations BMC Genomics Frontotemporal lobar degeneration TDP-43 microRNA progranulin |
author_facet |
Kocerha Jannet Kouri Naomi Baker Matt Finch NiCole DeJesus-Hernandez Mariely Gonzalez John Chidamparam Kumaravel Josephs Keith A Boeve Bradley F Graff-Radford Neill R Crook Julia Dickson Dennis W Rademakers Rosa |
author_sort |
Kocerha Jannet |
title |
Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations |
title_short |
Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations |
title_full |
Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations |
title_fullStr |
Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations |
title_full_unstemmed |
Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations |
title_sort |
altered microrna expression in frontotemporal lobar degeneration with tdp-43 pathology caused by progranulin mutations |
publisher |
BMC |
series |
BMC Genomics |
issn |
1471-2164 |
publishDate |
2011-10-01 |
description |
<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (<it>PGRN</it>) gene.</p> <p>Results</p> <p>Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying <it>PGRN </it>mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of <it>PGRN </it>mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.</p> <p>Conclusions</p> <p>Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by <it>PGRN </it>mutations and provides new insight into potential future therapeutic options.</p> |
topic |
Frontotemporal lobar degeneration TDP-43 microRNA progranulin |
url |
http://www.biomedcentral.com/1471-2164/12/527 |
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