Autosomal recessive primary microcephaly (MCPH, MIM 251200) is a neurodevelopmental disorder that results from a loss of neural progenitors in the embryonic neocortex. Patients with
MCPH have a significantly small brain and exhibit reduced cognition. MCPH is a genetically heterogeneous disease involving mutations in thirteen genes, nine of which centrosome protein-coding
genes, one of which is CDK5RAP2. The centrosome is the major microtubule organizing center in all animal cells. While MCPH is a neural stem cell disease, the molecular mechanisms for the
disease remains unknown. Proteomic analysis of a mutant in the Drosophila CDK5RAP2 ortholog, centrosomin (cnn), we discovered proteins involved in intermediary metabolism, oxidative stress,
and inherited Parkinson's disease that were post-translationally modified in mutant brains relative to wild type brains. These findings led us to discover that cnn mutants have neurological
defects, including poor locomotor and flight performance, and are less active. We further demonstrated that cnn and Sas-4 (MCPH6/CPAP in human) mutant cells have elevated reactive oxygen
species (ROS) levels, chronically activating the Jun N-terminal kinase (JNK) stress signaling pathway and thus activating FOXO by nuclear localization. The cause for these stress responses
appears to be due to a severe deficiency in autophagy induction in MCPH mutant cells. Autophagy is a major catabolic pathway for the degradation of damaged proteins and organelles. Here we
show that MCPH proteins are required for autophagy induction and act downstream of mechanistic target of rapamycin (mTOR) kinase, a negative regulator of autophagy. Together these results
demonstrate a novel function for MCPH genes in oxidative stress and regulating autophagy. / A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester, 2014. / November 7, 2014. / autophagy, centrosome, microcephaly, oxidative stress / Includes bibliographical references. / Timothy Megraw, Professor Directing Dissertation; Yoichi Kato, Committee Member; Branko Stefanovic, Committee Member; Yanchang Wang, Committee
Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_253396 |
| Contributors | Cabrera, Oscar Alexander (authoraut), Megraw, Timothy L. (professor directing dissertation), Deng, Wu-Min (university representative), Kato, Yoichi (committee member), Stefanovic, Branko (committee member), Wang, Yanchang (committee member), Florida State University (degree granting institution), College of Medicine (degree granting college), College of Medicine (degree granting department) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource (81 pages), computer, application/pdf |
| Rights | This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). The copyright in theses and dissertations completed at Florida State University is held by the students who author them. |
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