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

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.

journal_name

BMC Genomics

journal_title

BMC genomics

authors

Kocerha J,Kouri N,Baker M,Finch N,DeJesus-Hernandez M,Gonzalez J,Chidamparam K,Josephs KA,Boeve BF,Graff-Radford NR,Crook J,Dickson DW,Rademakers R

doi

10.1186/1471-2164-12-527

subject

Has Abstract

pub_date

2011-10-27 00:00:00

pages

527

issn

1471-2164

pii

1471-2164-12-527

journal_volume

pub_type

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