Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations

Jannet Kocerha, Naomi Kouri, Matt Baker, NiCole Finch, Mariely DeJesus-Hernandez, John Gonzalez, Kumaravel Chidamparam, Keith Anthony Josephs, Bradley F Boeve, Neill R Graff Radford, Juliana Crook, Dennis W Dickson, Rosa V Rademakers

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: 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 (PGRN) gene.Results: 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 PGRN 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 PGRN 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.Conclusions: Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and provides new insight into potential future therapeutic options.

Original languageEnglish (US)
Article number527
JournalBMC Genomics
Volume12
DOIs
StatePublished - Oct 27 2011

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Frontotemporal Lobar Degeneration
MicroRNAs
Pathology
Mutation
Frontal Lobe
Real-Time Polymerase Chain Reaction
Genes
Messenger RNA
Cerebellar Cortex
Angiogenesis Inhibitors
DNA-Binding Proteins
Neurodegenerative Diseases
Synapses

Keywords

  • Frontotemporal lobar degeneration
  • Microrna
  • Progranulin
  • Tdp-43

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations. / Kocerha, Jannet; Kouri, Naomi; Baker, Matt; Finch, NiCole; DeJesus-Hernandez, Mariely; Gonzalez, John; Chidamparam, Kumaravel; Josephs, Keith Anthony; Boeve, Bradley F; Graff Radford, Neill R; Crook, Juliana; Dickson, Dennis W; Rademakers, Rosa V.

In: BMC Genomics, Vol. 12, 527, 27.10.2011.

Research output: Contribution to journalArticle

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AU - Baker, Matt

AU - Finch, NiCole

AU - DeJesus-Hernandez, Mariely

AU - Gonzalez, John

AU - Chidamparam, Kumaravel

AU - Josephs, Keith Anthony

AU - Boeve, Bradley F

AU - Graff Radford, Neill R

AU - Crook, Juliana

AU - Dickson, Dennis W

AU - Rademakers, Rosa V

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AB - Background: 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 (PGRN) gene.Results: 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 PGRN 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 PGRN 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.Conclusions: Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and provides new insight into potential future therapeutic options.

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