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| Laboratory Address: |
Laboratory
Gonda 6554
Los Angeles, CA 90095
UNITED STATES
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| Work Address: |
Gonda 6357B
Los Angeles, CA 90095
UNITED STATES
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| Work Address: |
Office
Gonda 6357B
UNITED STATES
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Work Phone Number:
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310-206-2148
Laboratory
310-206-3749
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Genetic Disorders of Organelle Biogenesis and Protein Trafficking
The goal of this laboratory is to understand the molecular bases of human diseases that affect the biogenesis of intracellular organelles. Current efforts are focused on the study of Hermansky-Pudlak syndrome (HPS), a genetic disorder characterized by albinism and prolonged bleeding due to deficiencies in two intracellular organelles: melanosomes (the site of synthesis and storage of melanin pigments) and platelet dense granules (the storage compartment for some of the molecules involved in platelet aggregation). Both melanosomes and platelet dense granules are referred to as "lysosome-related organelles" and are believed to share with lysosomes common biogenesis pathways.
It has recently become apparent that HPS in humans and mice can arise from mutations in a number of genes. The products of these genes are expected to play a role in the formation of lysosomes and related organelles, although the mechanisms of this important biological process remain unclear. Interestingly, some of the genes identified so far encode components of the molecular machinery that mediates intracellular protein trafficking (e.g., the beta3A subunit of the AP-3 sorting adaptor complex). Other HPS genes, however, encode novel proteins of unknown function. In this laboratory, we are studying the structural and functional properties of these proteins by using biochemical and cell biological techniques together with genetics in animal models of the disease. We have found that these novel HPS gene products are subunits of three distinct protein complexes, which we have named BLOC (Biogenesis of Lysosome-related Organelles Complex)-1, -2 and -3. We are currently studying the molecular function of each BLOC.
Intriguingly, genetic variations in the gene encoding the dysbindin subunit of BLOC-1 have been associated with an increased risk of developing schizophrenia, a common psychiatric disorder with significant, but complex, genetic involvement. In collaboration with other laboratories, we are trying to determine whether BLOC-1 plays specific functions in brain that would be consistent with a direct role in the pathogenesis of schizophrenia.
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Esteban C. Dell'Angelica was trained as a biochemist at the University of Buenos Aires (Buenos Aires, Argentina), where he got his Ph.D. degree for his structural and functional characterization of a novel calcium-binding protein highly abundant in circulating neutrophils. Subsequently, he joined as a postdoctoral fellow the laboratory of Juan S. Bonifacino, Ph.D., at the National Institutes of Health (Bethesda, Maryland), to study the molecular machinery that regulates intracellular protein trafficking and the biogenesis of organelles of the late secretory and endocytic pathways. During this work, he described the first example of human disease due to mutations in a known component of the protein trafficking machinery. In 2000 he joined the faculty of the Department of Human Genetics at UCLA to focus his studies on genetic disorders that affect protein trafficking and organelle biogenesis.
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Ghiani CA, Starcevic M, Rodriguez-Fernandez IA, Nazarian R, Cheli VT, Chan LN, Malvar JS, de Vellis J, Sabatti C, Dell'Angelica EC The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth..
Molecular Psychiatry.
2010; 15:
204–215.
Rodriguez-Fernandez IA, Dell'Angelica EC A data-mining approach to rank candidate protein-binding partners--The case of biogenesis of lysosome-related organelles complex-1 (BLOC-1)..
Journal of Inherited Metabolic Disorders.
2009; 32:
190-203.
Nazarian R, Huizing M, Helip-Wooley A, Starcevic M, Gahl WA, Dell'Angelica EC An immunoblotting assay to facilitate the molecular diagnosis of Hermansky-Pudlak syndrome..
Molecular Genetics and Metabolism.
2008; 93:
134-144.
Falcon-Perez JM, Dell'Angelica EC Zinc transporter 2 (SLC30A2) can suppress the vesicular zinc defect of adaptor protein 3-depleted fibroblasts by promoting zinc accumulation in lysosomes..
Experimental Cell Research.
2007; 313:
1473-1483.
Falcon-Perez JM, Romero-Calderon R, Brooks ES, Krantz DE, Dell'Angelica EC The Drosophila pigmentation gene pink (p) encodes a homologue of human Hermansky-Pudlak syndrome 5 (HPS5)..
Traffic.
2007; 15:
154-168.
Dell'Angelica EC Bad signals jam organelle traffic..
Nature Medicine
2007; 13:
31-32.
Di Pietro SM, Falcon-Perez JM, Tenza D, Setty SRG, Marks MS, Raposo G, Dell'Angelica EC BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes..
Molecular Biology of the Cell.
2006; 17:
4027-4038.
Nazarian R, Starcevic M, Spencer MJ, Dell'Angelica EC Reinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein..
Biochemical Journal.
2006; 395:
587-598.
Falcon-Perez JM, Nazarian R, Sabatti C, Dell'Angelica EC Distribution and dynamics of Lamp1-containing endocytic organelles in fibroblasts deficient in biogenesis of lysosome-related organelles complex-3 (BLOC-3)..
The Journal of Cell Science.
2005; 118:
5243-5255.
Di Pietro SM, Dell'Angelica EC The cell biology of Hermansky-Pudlak syndrome: recent advances..
Traffic.
2005; 6:
525-533.
Dell'Angelica EC The building BLOC(k)s of lysosomes and related organelles..
Current Opinion in Cell Biology
2004; 16:
458-464.
Starcevic M, Dell'Angelica EC Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1)..
The Journal of Biological Chemistry.
2004; 279:
28393-28401.
Di Pietro SM, Falcon-Perez JM, Dell'Angelica EC Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6..
Traffic.
2004; 5:
276-283.
Dell'Angelica EC Melanosome biogenesis: shedding light on the origin of an obscure organelle..
Trends in Cell Biology
2003; 13:
503-506.
Nazarian R, Falcon-Perez JM, Dell'Angelica EC Biogenesis of lysosome-related organelles complex 3 (BLOC-3): A complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4..
Proceedings of the National Academy of Sciences USA.
2003; 100:
8770-8775.
Starcevic M, Nazarian R, Dell'Angelica, EC The molecular machinery for the biogenesis of lysosome-related organelles: lessons from Hermansky-Pudlak syndrome..
Seminars in cell & developmental biology.
2002; 13:
271-278.
Falcon-Perez JM, Starcevic M, Gautam R, Dell'Angelica EC BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet dense granules..
The Journal of Biological Chemistry.
2002; 277:
28191-28199.
Falcon-Perez JM, Dell'Angelica EC The pallidin (Pldn) gene and the role of SNARE proteins in melanosome biogenesis..
Pigment Cell Research
2002; 15:
82-86.
Dell'Angelica EC, Payne GS Intracellular cycling of lysosomal enzyme receptors: cytoplasmic tails' tales..
Cell
2001; 106:
395-398.
Dell'Angelica EC Clathrin-binding proteins: Got a motif? Join the network!.
Trends in Cell Biology
2001; 11:
315-318.
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