The Regulatory Role of microRNAs in the Mouse and Human Brain

microRNAs (miRNAs) are 20-24 nucleotides small, single-stranded, non-coding RNAs. They associate with Argonaute (AGO) proteins and exert their function by inhibition or degradation of messenger RNAs. A single miRNA can target hundreds of genes and one gene can be targeted by several miRNAs, hereby giving rise to a complex post-transcriptional network. In the brain, hundreds of miRNAs are expressed and several are implicated in the regulation of important neuronal functions and neurodegenerative diseases. However, many questions remain concerning the regulatory role of miRNAs in the brain.
The first part of this thesis is focused on the role of miRNAs in adult neurogenesis. We show that miR-125 controls functional integration of adult-born interneurons into the olfactory bulb (OB) (paper 1) and that let-7 is the most abundant miRNA in newborn OB interneurons (paper 2). Moreover, we demonstrate that let-7 controls radial migration of newborn neurons through positive regulation of neuronal autophagy, thereby revealing a novel link between miRNAs and autophagy in adult neurogenesis. This finding led us to explore whether autophagy and miRNA regulation are also linked in neurodegenerative diseases, such as Huntington’s disease (HD), where autophagy is commonly impaired. We show that in several models of HD and in post-mortem brain tissue of HD patients, impaired autophagy leads to the accumulation of AGO2. This AGO2 accumulation results in increased levels of miRNAs with severe consequences on post-transcriptional regulation (paper 3). Finally, the work in this thesis revealed transposable elements as important sources for miRNAs and their target sites in both the developing and adult human brain (paper 4). Together, the studies in this thesis extend our current knowledge on the role of miRNAs in the brain, and ultimately provide an insight into how disturbances in miRNA regulation can have severe consequences on neuronal functions.