Schizophrenia: The "BLOC" May Be in the Endosomes

• Type of Material: Article
• Authors: Pearl V. Ryder, Emory University; Victor Faundez, Emory University
• Language: English
• Date: 2009-10-20
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright 2008 by the American Association for the Advancement of Science; all rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/scisignal.293pe66
• Title of Journal or Parent Work: Science Signaling
• ISSN: 1945-0877
• Volume: 2
• Issue: 93
• Start Page: pe66
• End Page: pe66
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health to V.F. (NS42599) and T32 GM008367, National Institutes of Health, Training Program in Biochemistry, Cell, and Molecular Biology to P.V.R.
• Keywords: Life Sciences & Biomedicine; COMPLEX; LYSOSOME-RELATED ORGANELLES; CELL BIOLOGY; ENDOCYTIC PATHWAY; HIPPOCAMPAL-FORMATION; Biochemistry & Molecular Biology; Science & Technology; Cell Biology; PROTEIN; TRAFFICKING; HERMANSKY-PUDLAK-SYNDROME; COMMON VARIANTS; ACETYLCHOLINE-RECEPTOR
• Research Categories: Biology, Cell; Chemistry, Biochemistry; Biology, Neuroscience

Abstract

Genome-wide association studies have identified multiple genetic polymorphisms associated with schizophrenia. These polymorphisms conform to a polygenic disease model in which multiple alleles cumulatively increase the risk of developing disease. Two genes linked to schizophrenia, DTNBP1 and MUTED, encode proteins that belong to the endosome-localized Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1). BLOC-1 plays a key role in endosomal trafficking and as such has been found to regulate cell-surface abundance of the D2 dopamine receptor, the biogenesis and fusion of synaptic vesicles, and neurite outgrowth. These functions are pertinent to both neurodevelopment and synaptic transmission, processes tightly regulated by selective cell-surface delivery of membrane proteins to and from endosomes. We propose that cellular processes, such as endosomal trafficking, act as convergence points in which multiple small effects from polygenic genetic polymorphisms accumulate to promote the development of schizophrenia.