2008 Brain Star Award Recipient - Reuben Saba
Recipient
Reuben Saba - Biosketch
PhD candidate
University of Manitoba
Article
Citation: Saba R, Goodman CD, Huzarewich RLCH, Robertson C, Booth SA (2008) A miRNA Signature of Prion Induced Neurodegeneration. PLoS ONE 3(11): e3652. doi:10.1371/journal.pone.
Significance of the paper
Prion diseases or Transmissible Spongiform Encephalopathies (TSE) are an invariably fatal class of neurodegenerative diseases that affects both humans and animals. The most well known among the TSEs is Bovine Spongiform Encephalopathies (BSE) or 'mad cow disease'. Prion diseases, in general, are caused by the misfolding of a ubiquitously expressed host protein, PrPc, to an aberrant isoform, PrPSc, which has a tendency to self-replicate and aggregate, in the process forming protease-resistant amyloid plaques in the brain which in turn leads to neuronal loss. Presently, the molecular mechanism(s) involved in PrPc misfolding and the disease process are poorly characterized.
MicroRNAs (miRNAs) are a small (~22 nucleotides long), non-coding RNA molecules that have recently emerged as a master class of gene regulatory molecules. To date, several hundred miRNAs have been identified in humans. Many of the miRNAs are highly conserved between many vertebrate species. MiRNAs are involved in the post-transcriptional regulation of protein-coding mRNA by binding to complementary regions in the 3'UTR which in turn leads to either transcript degradation or translation repression. Each miRNA has the potential to target hundreds of target genes. To date, miRNAs have been implicated in both development and disease.
In this paper, we show the first evidence for the altered abundance of these molecules in the brains of mice infected with a mouse-adapted, prion disease when compared to mock-infected mice. We then went onto determined the target genes regulated by the altered miRNAs using a combination of experimental and bioinformatic approaches and identified that genes previously implicated to be altered in prion disease have the potential to be also regulated by some of the miRNAs identified in this study. In general, miRNAs identified in this study have the potential to regulate genes involved in cell death, neuronal function and neurogenesis. This study identifies an important hierarchical level of gene regulation that has previously gone unrecognized and adds another piece to the prion puzzle.
Overall, the results presented in this paper constitutes the first ever evidence for the de-regulation of miRNAs in prion-diseases and one of the first to demonstrate it within the spectrum of neurodegenerative diseases. Since each miRNA has the potential to target hundreds of target genes, then it is possible to use these molecules as a point of therapeutic intervention by modulating the expression of some of the aberrantly expressed miRNAs either by knock-out or over-expression strategies.