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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.
Includes bibliographical references.
Timothy Megraw, Professor Directing Dissertation; Yoichi Kato, Committee Member; Branko Stefanovic, Committee Member; Yanchang Wang, Committee Member.
Florida State University
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