miR-107 Regulates Granulin/Progranulin with Implications for Traumatic Brain Injury and Neurodegenerative Disease
Granulin (GRN, or progranulin) is a protein involved in wound repair, inflammation, and neoplasia. GRN has also been directly implicated in frontotemporal dementia and may contribute to Alzheimer’s disease pathogenesis. However, GRN regulation expression is poorly understood. A high-throughput experimental microRNA assay showed that GRN is the strongest target for miR-107 in human H4 neuroglioma cells. miR-107 has been implicated in Alzheimer’s disease pathogenesis, and sequence elements in the open reading frame—rather than the 3′ untranslated region—of GRN mRNA are recognized by miR-107 and are highly conserved among vertebrate species. To better understand the mechanism of this interaction, FLAG-tagged Argonaute constructs were used following miR-107 transfection. GRN mRNA interacts preferentially with Argonaute 2. In vitro and in vivo studies indicate that regulation of GRN by miR-107 may be functionally important. Glucose supplementation in cultured cells that leads to increased miR-107 levels also results in decreased GRN expression, including changes in cell compartmentation and decreased secretion of GRN protein. This effect was eliminated following miR-107 transfection. We also tested a mouse model where miR-107 has been shown to be down-regulated. In brain tissue subjacent to 1.0 mm depth controlled cortical impact, surviving hippocampal neurons show decreased miR-107 with augmentation of neuronal GRN expression. These findings indicate that miR-107 contributes to GRN expression regulation with implications for brain disorders.
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Supported by grants R01 NS061933, K08 NS050110, and P30 AG028383 from NIH, and Kentucky Spinal Cord and Head Injury Research Trust grant 7–20.
Supplemental material for this article can be found on http://ajp.amjpathol.org .
Wang, Wang-Xia; Wilfred, Bernard R.; Madathil, Sindhu K.; Tang, Guiliang; Hu, Yanling; Dimayuga, James; Stromberg, Arnold J.; Huang, Qingwei; Saatman, Kathryn E.; and Nelson, Peter T., "miR-107 Regulates Granulin/Progranulin with Implications for Traumatic Brain Injury and Neurodegenerative Disease" (2010). Pathology and Laboratory Medicine Faculty Publications. 22.