Altered microRNA Expression in Frontotemporal Lobar Degeneration With TDP-43 Pathology Caused by Progranulin Mutations

BMC Genomics. 2011 Oct 27;12:527. doi: 10.1186/1471-2164-12-527.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • DNA-Binding Proteins / metabolism*
  • Female
  • Frontal Lobe / metabolism
  • Frontal Lobe / pathology
  • Frontotemporal Lobar Degeneration / genetics*
  • Frontotemporal Lobar Degeneration / pathology
  • Gene Expression Profiling
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Progranulins
  • Protein Precursors / genetics

Substances

  • DNA-Binding Proteins
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • MicroRNAs
  • Progranulins
  • Protein Precursors

Associated data

  • GEO/GDS3459