Open Access Research article

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

Jannet Kocerha1, Naomi Kouri1, Matt Baker1, NiCole Finch1, Mariely DeJesus-Hernandez1, John Gonzalez1, Kumaravel Chidamparam2, Keith A Josephs3, Bradley F Boeve3, Neill R Graff-Radford4, Julia Crook1, Dennis W Dickson1 and Rosa Rademakers1*

Author Affiliations

1 Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA

2 Ocean Ridge Biosciences, 10475 Riverside Drive, Suite 1, Palm Beach Gardens, FL 33410, USA

3 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

4 Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA

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BMC Genomics 2011, 12:527  doi:10.1186/1471-2164-12-527

Published: 27 October 2011

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.

Keywords:
Frontotemporal lobar degeneration; TDP-43; microRNA; progranulin