دورية أكاديمية
أعرض في EDS

A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination.

التفاصيل البيبلوغرافية
العنوان: A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination.
المؤلفون: Bai Q; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA., Shao E; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Tsinghua University School of Medicine, Beijing, China., Ma D; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA., Jiao B; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Tsinghua University School of Medicine, Beijing, China., Scheetz SD; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA., Hartnett-Scott KA; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA., Ilin VA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA., Aizenman E; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA., Kofler J; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA., Burton EA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA. eab25@pitt.edu.; Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA, 15213, USA. eab25@pitt.edu.; Geriatrics Research, Education and Clinical Center, Pittsburgh VA Healthcare System, Pittsburgh, PA, 15240, USA. eab25@pitt.edu.
المصدر: Nature communications [Nat Commun] 2024 Sep 18; Vol. 15 (1), pp. 8195. Date of Electronic Publication: 2024 Sep 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Zebrafish* , Transcription Factors*/metabolism , Transcription Factors*/genetics , tau Proteins*/metabolism , tau Proteins*/genetics , Animals, Genetically Modified* , Microglia*/metabolism , Microglia*/pathology , Disease Models, Animal* , Synapses*/metabolism , Supranuclear Palsy, Progressive*/metabolism , Supranuclear Palsy, Progressive*/genetics , Supranuclear Palsy, Progressive*/pathology, Animals ; Humans ; Azepines/pharmacology ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics ; Triazoles/pharmacology ; Rats ; Zebrafish Proteins/metabolism ; Zebrafish Proteins/genetics ; Brain/metabolism ; Brain/pathology ; Phagocytosis ; Neurons/metabolism ; Bromodomain Containing Proteins ; Cell Cycle Proteins
مستخلص: Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4 +/- mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
References: Neurosci Lett. 2018 Apr 3;671:33-37. (PMID: 29410359)
Glia. 2020 Feb;68(2):298-315. (PMID: 31508850)
Neuron. 2018 Dec 19;100(6):1337-1353.e5. (PMID: 30415998)
Dev Dyn. 2008 Jun;237(6):1636-44. (PMID: 18498094)
Sci Rep. 2019 Jul 16;9(1):10280. (PMID: 31311960)
Mol Neurodegener. 2018 Jul 9;13(1):37. (PMID: 29986742)
Nat Rev Drug Discov. 2019 Aug;18(8):609-628. (PMID: 31273347)
Acta Neuropathol Commun. 2019 Jul 5;7(1):107. (PMID: 31277703)
Nat Med. 2021 Aug;27(8):1451-1457. (PMID: 34385707)
J Alzheimers Dis. 2009;18(2):305-17. (PMID: 19584432)
Ann Neurol. 2020 Dec;88(6):1194-1204. (PMID: 32951237)
Brain Pathol. 2021 Jul;31(4):e12914. (PMID: 33089580)
Brain Pathol. 2007 Jan;17(1):74-82. (PMID: 17493041)
J Neuropathol Exp Neurol. 2001 May;60(5):403-10. (PMID: 11379815)
Elife. 2020 Mar 17;9:. (PMID: 32180546)
Brain. 2007 Jun;130(Pt 6):1552-65. (PMID: 17405767)
J Neurochem. 1997 May;68(5):1836-45. (PMID: 9109508)
Cell. 2008 May 30;133(5):916-27. (PMID: 18510934)
Biochim Biophys Acta. 2011 Mar;1812(3):353-63. (PMID: 20849952)
Hum Mol Genet. 2020 Jan 15;29(2):202-215. (PMID: 31696228)
Redox Biol. 2020 Oct;37:101695. (PMID: 32905883)
Sci Transl Med. 2017 May 31;9(392):. (PMID: 28566429)
Oxf Open Neurosci. 2023 Jan 06;2:kvac018. (PMID: 37649777)
J Neurosci Methods. 2018 Jan 01;293:329-337. (PMID: 29042258)
Sci Rep. 2017 Oct 11;7(1):12959. (PMID: 29021554)
Arch Neurol. 1964 Apr;10:333-59. (PMID: 14107684)
Neuron. 2018 Dec 19;100(6):1322-1336.e7. (PMID: 30392797)
Hum Mol Genet. 1999 Apr;8(4):711-5. (PMID: 10072441)
J Cell Mol Med. 2019 May;23(5):3214-3223. (PMID: 30809946)
Cell Biosci. 2018 Nov 20;8:60. (PMID: 30479742)
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10032-7. (PMID: 12888622)
J Neurosci. 2021 May 5;41(18):4141-4157. (PMID: 33731451)
Neurobiol Dis. 2011 Oct;44(1):9-18. (PMID: 21669287)
Mov Disord. 2014 Apr;29(4):470-8. (PMID: 24532007)
J Clin Invest. 2009 May;119(5):1382-95. (PMID: 19363289)
Nat Genet. 2011 Jun 19;43(7):699-705. (PMID: 21685912)
Cell Rep. 2019 Aug 20;28(8):2111-2123.e6. (PMID: 31433986)
J Neurosci Res. 1997 Apr 15;48(2):128-32. (PMID: 9130141)
Nat Rev Neurol. 2021 Oct;17(10):601-620. (PMID: 34426686)
Nat Rev Drug Discov. 2011 Jun 24;10(7):507-19. (PMID: 21701501)
Science. 2016 May 6;352(6286):712-716. (PMID: 27033548)
Dev Comp Immunol. 2014 Sep;46(1):3-10. (PMID: 24462834)
Acta Neuropathol. 2015 Sep;130(3):349-62. (PMID: 26150341)
Brain. 2017 Apr 1;140(4):1128-1146. (PMID: 28334843)
Blood. 2011 Jan 27;117(4):e49-56. (PMID: 21084707)
J Neurochem. 1999 Mar;72(3):1243-9. (PMID: 10037497)
Sci Total Environ. 2020 Mar 20;709:134490. (PMID: 31905542)
ACS Med Chem Lett. 2019 Apr 24;10(6):1002-1006. (PMID: 31223462)
Curr Alzheimer Res. 2016;13(9):985-95. (PMID: 27117003)
Front Toxicol. 2021 Dec 21;3:804033. (PMID: 35295145)
Nat Commun. 2018 Jul 26;9(1):2929. (PMID: 30050033)
Nature. 2010 Dec 23;468(7327):1067-73. (PMID: 20871596)
Nucleic Acids Res. 2007;35(19):6501-16. (PMID: 17897967)
Curr Neuropharmacol. 2018;16(10):1484-1498. (PMID: 29318974)
Nat Protoc. 2014 Jul;9(7):1533-48. (PMID: 24901738)
J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):441-5. (PMID: 20360166)
Acta Neuropathol. 2022 Oct;144(4):603-614. (PMID: 35947184)
EMBO J. 2019 Apr 1;38(7):. (PMID: 30842097)
J Biol Chem. 2014 Aug 29;289(35):24114-28. (PMID: 25028515)
Sci Transl Med. 2023 Mar 29;15(689):eadf0141. (PMID: 36989373)
J Neurosci Res. 2002 Dec 15;70(6):734-45. (PMID: 12444595)
Hum Mol Genet. 2006 Dec 15;15(24):3529-37. (PMID: 17085483)
Nature. 1998 Jun 18;393(6686):702-5. (PMID: 9641683)
Mol Cell Biol. 2009 Mar;29(5):1375-87. (PMID: 19103749)
Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1255-60. (PMID: 18202183)
Acta Neuropathol. 2001 Feb;101(2):167-73. (PMID: 11271372)
Neurobiol Dis. 2016 Nov;95:238-49. (PMID: 27452482)
Brain. 2022 Mar 29;145(1):340-348. (PMID: 34398211)
Lancet Neurol. 2021 Mar;20(3):182-192. (PMID: 33609476)
J Physiol. 2011 Aug 1;589(Pt 15):3703-8. (PMID: 21646414)
J Neurosci Res. 2022 Nov;100(11):2044-2054. (PMID: 35986577)
Science. 2020 Mar 6;367(6482):. (PMID: 32139519)
Science. 2001 Jul 27;293(5530):711-4. (PMID: 11408621)
Nat Methods. 2012 Jul;9(7):671-5. (PMID: 22930834)
Neuron. 2007 Feb 1;53(3):337-51. (PMID: 17270732)
J Neurosci Res. 1994 Dec 15;39(6):669-73. (PMID: 7534834)
Front Pharmacol. 2021 Jan 26;11:621093. (PMID: 33574760)
J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1386-94. (PMID: 15377682)
Acta Neuropathol Commun. 2023 Mar 11;11(1):40. (PMID: 36906636)
Nat Commun. 2023 Nov 2;14(1):6801. (PMID: 37919278)
Mov Disord. 2019 Jul;34(7):1049-1059. (PMID: 31059154)
Genesis. 2007 Oct;45(10):625-9. (PMID: 17941043)
Oxf Open Neurosci. 2023;2:. (PMID: 37637775)
J Neuroinflammation. 2020 May 11;17(1):155. (PMID: 32393376)
PLoS Genet. 2012;8(4):e1002638. (PMID: 22511881)
J Cardiovasc Transl Res. 2017 Aug;10(4):337-347. (PMID: 28567671)
J Biol Chem. 2022 Apr;298(4):101794. (PMID: 35248531)
Nature. 2010 Apr 22;464(7292):1201-4. (PMID: 20357768)
معلومات مُعتمدة: R01 NS043277 United States NS NINDS NIH HHS; AG066468 U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging); NS123211 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); R56 NS043277 United States NS NINDS NIH HHS; R21 NS123211 United States NS NINDS NIH HHS; I01 BX003168 United States BX BLRD VA; NS080881 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); 655-2018-06 CurePSP; P30 AG066468 United States AG NIA NIH HHS; R21 NS080881 United States NS NINDS NIH HHS; NS043277 U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); BX003168 U.S. Department of Veterans Affairs (Department of Veterans Affairs); 468-08 CurePSP
المشرفين على المادة: 0 (Transcription Factors)
0 (tau Proteins)
0 (BRD4 protein, human)
0 (Azepines)
0 (Nuclear Proteins)
0 (Triazoles)
0 ((+)-JQ1 compound)
0 (MAPT protein, human)
0 (Zebrafish Proteins)
0 (Bromodomain Containing Proteins)
0 (Cell Cycle Proteins)
تواريخ الأحداث: Date Created: 20240918 Date Completed: 20240918 Latest Revision: 20240922
رمز التحديث: 20240922
مُعرف محوري في PubMed: PMC11410960
DOI: 10.1038/s41467-024-52173-0
PMID: 39294122
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-52173-0