Autophagy is a critical cell physiological metabolic response to nutrient deprivation and a variety of stresses. The mechanics of autophagy, involving the formation and trafficking of autophagic vesicular structures, requires microtubules but this requirement is poorly understood. Centrosomes, the major microtubule-organizing centers (MTOCs) in animal cells, organize microtubules to accomplish essential cellular functions. While much is known regarding centrosome function in mitosis, little is understood about the requirements of centrosomes in interphase cells. In interphase cells, the microtubule array functions in intracellular transport and cell polarization for cell migration and differentiaed cell functions. The genes for at least nine centrosomal proteins are mutated in inherited microcephaly syndromes that impair brain development. The primary defect in these syndromes appears to be a failure of stem cell proliferation, but the cause for this and the centrosomal basis is unresolved. In this proposal, we will investigate autophagy as a new function for centrosomal proteins, implicating a new basis for microcephaly syndromes.
Two specific aims will achieve these goals.
Our first aim i s to determine how two centrosome proteins, centrosomin and sas-4, regulate autophagy.
The second aim i s to determine how a novel partner of centrosomin stimulates autophagy. Our broader objective with these aims is to understand how centrosome proteins regulate autophagy, and whether autophagy is required for neural stem cells to proliferate and differentiate normally. Understanding these processes will advance our understanding of the basis of MCPH disease and of the basic requirements of centrosomes to regulate autophagy.
Centrosomes, found in nearly all human cells, are macromolecular complexes that organize cytoskeleton for structural integrity and for polarized transport of molecules, vesicles and organelles to control developmental and physiological processes. Genes that encode centrosome proteins are mutated in human disorders that affect stem cells, stunting development of the brain and/or the whole body, leading to microcephaly and primordial dwarfism in affected individuals. The goal of this proposal is to determine the functions of centrosome proteins in the cell-protective process of autophagy.
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|Zheng, Yiming; Mennella, Vito; Marks, Steven et al. (2016) The Seckel syndrome and centrosomal protein Ninein localizes asymmetrically to stem cell centrosomes but is not required for normal development, behavior, or DNA damage response in Drosophila. Mol Biol Cell 27:1740-52|