Dysbindin

Dysbindin was discovered by the research group of Derek Blake via yeast two-hybrid screening for binding partners of α-dystrobrevin.{{cite journal | vauthors = Benson MA, Newey SE, Martin-Rendon E, Hawkes R, Blake DJ | title = Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain | journal = Journal of Biological Chemistry | volume = 276 | issue = 26 | pages = 24232–24241 | date = Jun 2001 | pmid = 11316798 | doi = 10.1074/jbc.M010418200 | doi-access = free }}

Dysbindin is found in neural tissue of the brain, particularly in axon bundles and especially in certain axon terminals, notably mossy fiber synaptic terminals in the cerebellum and hippocampus.

Dysbindin is a coiled-coil-containing protein that serves as a core, stable component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1), a multisubunit complex involved in intracellular protein trafficking and synaptic function.{{cite journal | vauthors = Saakian DB, Hu CK | title = Exact solution of the Eigen model with general fitness functions and degradation rates | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 13 | pages = 4935–4939 | date = March 2006 | pmid = 16549804 | pmc = 1458773 | doi = 10.1073/pnas.0504924103 | doi-access = free | bibcode = 2006PNAS..103.4935S }} Structurally, dysbindin engages in direct interactions with other BLOC-1 subunits—pallidin, snapin, and muted—primarily through a 69-residue region that forms coiled-coil domains, which are critical for complex assembly and stability.{{cite journal | vauthors = Atluri VS, Tiwari S, Rodriguez M, Kaushik A, Yndart A, Kolishetti N, Yatham M, Nair M | title = Inhibition of Amyloid-Beta Production, Associated Neuroinflammation, and Histone Deacetylase 2-Mediated Epigenetic Modifications Prevent Neuropathology in Alzheimer's Disease in vitro Model | journal = Frontiers in Aging Neuroscience | volume = 11 | pages = 342 | date = 2019 | pmid = 32009938 | pmc = 6974446 | doi = 10.3389/fnagi.2019.00342 | doi-access = free }} Dysbindin’s sequence does not share significant identity with proteins of known function outside BLOC-1, but its acidic C-terminal region is homologous to domains found in other regulatory proteins, suggesting a role in recruiting or scaffolding additional protein partners (PMID 16533041). Within neurons, dysbindin and its BLOC-1 partners localize to endosomal and synaptic compartments, where they regulate the trafficking of synaptic vesicle proteins and surface expression of neurotransmitter receptors, processes fundamental to synaptic plasticity and neurotransmission.{{cite journal | vauthors = Tang BC, Dawson M, Lai SK, Wang YY, Suk JS, Yang M, Zeitlin P, Boyle MP, Fu J, Hanes J | title = Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 46 | pages = 19268–19273 | date = November 2009 | pmid = 19901335 | pmc = 2780804 | doi = 10.1073/pnas.0905998106 | doi-access = free }}

Dysbindin is a multifunctional regulatory protein highly expressed in the brain, where it plays a critical role in synaptic function, neurotransmitter release, and cognitive processes. As a core component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1), dysbindin is essential for the trafficking of synaptic vesicle proteins and the regulation of receptor surface expression, particularly dopamine D2 receptors in cortical neurons.{{cite journal | vauthors = Ji Y, Yang F, Papaleo F, Wang HX, Gao WJ, Weinberger DR, Lu B | title = Role of dysbindin in dopamine receptor trafficking and cortical GABA function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 46 | pages = 19593–19598 | date = November 2009 | pmid = 19887632 | pmc = 2780743 | doi = 10.1073/pnas.0904289106 | doi-access = free | bibcode = 2009PNAS..10619593J }} Reduced dysbindin expression leads to increased surface D2 receptor levels and altered excitability of prefrontal cortical microcircuits, effects that have been linked to cognitive deficits and the pathophysiology of schizophrenia.{{cite journal | vauthors = Fallgatter AJ, Ehlis AC, Herrmann MJ, Hohoff C, Reif A, Freitag CM, Deckert J | title = DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients--support for the glutamate hypothesis of schizophrenias | journal = Genes, Brain and Behavior | volume = 9 | issue = 5 | pages = 489–497 | date = July 2010 | pmid = 20180862 | doi = 10.1111/j.1601-183X.2010.00574.x }}{{cite journal | vauthors = Guo AY, Sun J, Riley BP, Thiselton DL, Kendler KS, Zhao Z | title = The dystrobrevin-binding protein 1 gene: features and networks | journal = Molecular Psychiatry | volume = 14 | issue = 1 | pages = 18–29 | date = January 2009 | pmid = 18663367 | pmc = 2859304 | doi = 10.1038/mp.2008.88 }} Additionally, dysbindin is involved in the regulation of glutamatergic and GABAergic neurotransmission, synapse formation, and maintenance, further underscoring its importance in neurodevelopment and synaptic plasticity.

In drosophila, dysbindin has been shown to be essential for neural plasticity.{{cite journal | vauthors = Dickman DK, Davis GW | title = The Schizophrenia Susceptibility Gene Dysbindin Controls Synaptic Homeostasis | journal = Science | location = New York, N.Y. | volume = 326 | issue = 5956 | pages = 1127–1130 | date = November 2009 | pmid = 19965435 | pmc = 3063306 | doi = 10.1126/science.1179685 | bibcode = 2009Sci...326.1127D | publication-place = New York, N.Y. }}

• {{cite web | title = Schizophrenia gene's role may be broader, more potent, than thought | date = November 19, 2009 | website = Phys.org | url = http://www.physorg.com/news177861724.html }}

Interest in dysbindin has grown from pedigree-based family association studies of schizophrenia, which found a strong correlation between a particular dysbindin allele and the clinical manifestation of the disease.{{cite journal | vauthors = Straub R, Jiang Y, MacLean C, Ma Y, Webb B, Myakishev M, Harris-Kerr C, Wormley B, Sadek H, Kadambi B, Cesare AJ, Gibberman A, Wang X, O'Neill FA, Walsh D, Kendler KS | title = Genetic Variation in the 6p22.3 Gene DTNBP1, the Human Ortholog of the Mouse Dysbindin Gene, Is Associated with Schizophrenia | journal = American Journal of Human Genetics | volume = 71 | issue = 2 | pages = 337–348 | date = Aug 2002 | pmid = 12098102 | pmc = 379166 | doi = 10.1086/341750 }} However, this genetic link has not been consistently replicated across all case-control samples, suggesting that different genetic subtypes of schizophrenia, with varying disease allele frequencies, exist in different populations. This phenomenon, known as genetic locus heterogeneity, is common among complex disorders with strong genetic components. Compounding this complexity, it is likely that multiple distinct mutations within the dysbindin gene contribute to schizophrenia. This situation, known as disease allele heterogeneity, helps explain why different markers in the dysbindin gene show associations in different study populations.

Although the precise mechanisms by which dysbindin contributes to brain dysfunction are not fully understood, evidence suggests functional consequences. One study reported that schizophrenia patients carrying a high-risk dysbindin haplotype exhibited deficits in visual processing.{{cite journal | vauthors = Donohoe G, Morris DW, De Sanctis P, Magno E, Montesi JL, Garavan HP, Robertson IH, Javitt DC, Gill M, Corvin AP, Foxe JJ | title = Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia | journal = Biological Psychiatry | volume = 63 | issue = 5 | pages = 484–489 | date = Mar 2008 | pmid = 17945199 | doi = 10.1016/j.biopsych.2007.07.022 | hdl = 2262/40654 | s2cid = 16722145 | hdl-access = free }} Another study demonstrated that reduced expression of DTNBP1 led to increased cell surface levels of dopamine D2 receptors, implicating dysbindin in dopaminergic signaling regulation.{{cite journal | vauthors = Iizuka Y, Sei Y, Weinberger DR, Straub RE | title = Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization | journal = The Journal of Neuroscience | volume = 27 | issue = 45 | pages = 12390–12395 | date = Nov 2007 | pmid = 17989303 | pmc = 6673263 | doi = 10.1523/JNEUROSCI.1689-07.2007 }}

In addition to its role in schizophrenia, mutations in the DTNBP1 gene have been shown to cause Hermansky–Pudlak syndrome type 7.{{cite journal | vauthors = Li W, Zhang Q, Oiso N, Novak EK, Gautam R, O'Brien EP, Tinsley CL, Blake DJ, Spritz RA, Copeland NG, Jenkins NA, Amato D, Roe BA, Starcevic M, Dell'Angelica EC, Elliott RW, Mishra V, Kingsmore SF, Paylor RE, Swank RT | title = Hermansky–Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) | journal = Nature Genetics | volume = 35 | issue = 1 | pages = 84–89 | date = Sep 2003 | pmid = 12923531 | pmc = 2860733 | doi = 10.1038/ng1229 }}

Dysbindin has been shown to interact with SNAPAP,{{cite journal | vauthors = Starcevic M, Dell'Angelica EC | title = 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) | journal = Journal of Biological Chemistry | volume = 279 | issue = 27 | pages = 28393–28401 | date = July 2004 | pmid = 15102850 | doi = 10.1074/jbc.M402513200 | doi-access = free }} MUTED and PLDN.

{{Reflist}}

• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hps GeneReviews/NCBI/NIH/UW entry on Hermansky–Pudlak syndrome]
• {{MeshName|Dysbindin}}

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