Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations.
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.
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Jannet
J
Kocerha
Naomi
N
Kouri
Matt
M
Baker
NiCole
N
Finch
Mariely
M
DeJesus-Hernandez
John
J
Gonzalez
Kumaravel
K
Chidamparam
Keith A
KA
Josephs
Bradley F
BF
Boeve
Neill R
NR
Graff-Radford
Julia
J
Crook
Dennis W
DW
Dickson
Rosa
R
Rademakers
D000368:Aged; D000369:Aged, 80 and over; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D000077153:Progranulins; D011498:Protein Precursors / Q000235:genetics
D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D000077153:Progranulins; D011498:Protein Precursors