The Regulatory Role of microRNAs in the Mouse and Human Brain
Author
Summary, in English
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.
Department/s
Publishing year
2017
Language
English
Full text
- Available as PDF - 18 MB
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Document type
Dissertation
Publisher
Lund University: Faculty of Medicine
Topic
- Neurosciences
Keywords
- microRNA
- Argonaute
- AGO-RIP
- let-7
- miR-125
- adult neurogenesis
- olfactory bulb
- autophagy
- transposable elements
- LINE-2
- Huntington’s disease
Status
Published
Research group
- Molecular Neurogenetics
Supervisor
ISBN/ISSN/Other
- ISBN: 978-91-7619-526-0
Defence date
27 October 2017
Defence time
09:00
Defence place
Segerfalksalen, Wallenberg Neuroscience Center, BMC A10, Sölvegatan 17, Lund.
Opponent
- Jørgen Kjems (Professor)