Premium
S3‐02‐03: Upregulation of micro RNA (miRNA) signaling in Alzheimer's disease (AD) and related neurological disorders
Author(s) -
Lukiw Walter,
Bhattacharjee Surjyadipta,
Li Yuan Y.,
Alexandrov Peter N.,
Pogue Aileen I.,
Zhao Yuhai
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1123
Subject(s) - microrna , biology , human brain , retinal , retina , regulator , rna , downregulation and upregulation , non coding rna , regulation of gene expression , gene , messenger rna , neuroscience , genetics , microbiology and biotechnology , biochemistry
the “miR-15/107 gene group”, may be of central relevance to Alzheimer’s disease (AD) biology. This is a group of ten mature miRNAs of which multiple are highly expressed in human brain and dysregulated in AD. Our long-range goal is to develop therapeutic strategies based on miRNA neurochemistry. As a prerequisite to achieving these therapies, we need to better understand basic aspects of how the miR-15/107 genes are regulated in human cells. We need more comprehensive data on “upstream” stimuli that cause altered miRNA expression, paired with high-throughput identification of their miRNA targets. We hypothesize that miR-15/107 dysregulation will interact with metabolic and genetic factors that also alter AD risk. Methods: We have used both tissue culture experiments and human brain tissue to test the signalling pathways involved with miR-15/107 miRNAs. These have included miRNA microarrays, qPCR experiments, and various tissue culture assays designed to assess the upstream regulators and downstream targets of miR-15/107 miRNAs. Results: We observe the following: 1) MiR-15/107 gene expression is specifically responsive to glucose metabolism and PPAR signalling. 2) MiR-15/107 miRNAs are dysregulated early in AD pathogenesis, before cell type changes (i.e., neuronal loss) is observed. 3) MiR-15/107 miRNAs are important to assess comprehensively (as opposed to being analyzed one-by-one) because miR-15/107 miRNA gene regulatory activities overlap strikingly. 4) MiR-15/107 miRNAs regulate specific neurodegenerative disease genes (including BACE1), linking miRNA expression with neurodegenerative disease pathology.5) We were surprised to discover that the strongest target for miR-107 is GRN, a frontotemporal dementia (FTD) risk gene not predicted to be a miR-107 target. Furthermore, the miR-107:GRN interaction occurs within the GRN mRNA coding sequence, which also was unexpected. Conclusions: The miR-15/107 gene group comprises highly expressed brain miRNAs whose functions are still largely unknown. However, we note that these genes appear to connect known upstream metabolic changes with downstream pathologies and we ultimately hope that these impactful small RNAs could represent a potential therapeutic target.