The centrosome is the major microtubule-organizing center in animals. Mutations in centrosomal genes cause primary microcephaly (MCPH), a neurological disorder characterized by smaller brain size due to insufficient neurogenesis, highlighting the importance of centrosome proteins in neural development and in maintaining neural health. Yet the etiological basis for MCPH and the role of centrosome proteins in its pathogenesis remains unclear. To explore the etiological basis of MCPH, we performed 2-D difference gel electrophoresis in combination with mass spectrometry to identify molecular signatures of MCPH mutant brains in Drosophila. Proteomic analysis led us to discover a novel role of centrosomal proteins-regulation of autophagy. Autophagy is a major means by which cells clear misfolded or aggregated proteins and damaged organelles that contribute to the decline of neuronal health. We show that mutations in two essential centrosome proteins in Drosophila, centrosomin (cnn) and sas-4, impair starvation-induced autophagy and accumulate dramatically more protein aggregates. Consistently, cnn mutant larvae and flies are much more sensitive to starvation and have poor locomotor function compared to wild-type. Transmission electron microscopy analysis showed that Cnn regulates early steps in the assembly of autophagosomes, the double membrane structures that deliver cargos for lysosomal degradation. Mechanistically, our preliminary data showed that Cnn could act through a novel partner protein, an E3 ubiquitin ligase, to regulate autophagy. Overexpression of this E3 ligase induces autophagy, reduces cell size and causes tissue degeneration dependent on its E3 ligase activity. These findings reveal a novel role of centrosomal proteins and implicate defective autophagy as a novel function for centrosome proteins and a novel etiological basis for MCPH.