PUBLICATION

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

Authors
Bai, Q., Shao, E., Ma, D., Jiao, B., Scheetz, S.D., Hartnett-Scott, K.A., Ilin, V.A., Aizenman, E., Kofler, J., Burton, E.A.
ID
ZDB-PUB-240919-7
Date
2024
Source
Nature communications   15: 81958195 (Journal)
Registered Authors
Burton, Edward A.
Keywords
none
MeSH Terms
  • Neurons/metabolism
  • Bromodomain Containing Proteins
  • Nuclear Proteins/genetics
  • Nuclear Proteins/metabolism
  • Phagocytosis
  • Cell Cycle Proteins
  • Disease Models, Animal*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Zebrafish*
  • Microglia*/metabolism
  • Microglia*/pathology
  • Humans
  • Animals, Genetically Modified*
  • Animals
  • Supranuclear Palsy, Progressive*/genetics
  • Supranuclear Palsy, Progressive*/metabolism
  • Supranuclear Palsy, Progressive*/pathology
  • Azepines/pharmacology
  • tau Proteins*/genetics
  • tau Proteins*/metabolism
  • Transcription Factors*/genetics
  • Transcription Factors*/metabolism
  • Synapses*/metabolism
  • Rats
  • Triazoles/pharmacology
  • Brain/metabolism
  • Brain/pathology
(all 28)
PubMed
39294122 Full text @ Nat. Commun.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gl22TgTransgenic Insertion
    nkuasgfp1aTgTransgenic Insertion
      psi1TgTransgenic Insertion
        pt423TgTransgenic Insertion
          pt425TgTransgenic Insertion
            pt433TgTransgenic Insertion
              pt434TgTransgenic Insertion
                pt435
                  		Small Deletion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  brd4CRISPR1-brd4CRISPR
                  brd4MO1-brd4MRPHLNO
                  brd4MO3-brd4MRPHLNO
                  1 - 3 of 3
                  Show
                  Fish
                  No data available
                  Antibodies
                  Name Type Antigen Genes Isotypes Host Organism
                  Ab1-casp3monoclonal
                    		IgGRabbit
                    Ab1-dlg4polyclonal
                      		IgGRabbit
                      Ab-4C4monoclonal
                        		IgG1Mouse
                        1 - 3 of 3
                        Show
                        Orthology
                        No data available
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        EGFPEFGEGFP
                        GAL4EFGGAL4
                        GAL4FFEFGGAL4FF
                        mCherryEFGmCherry
                        1 - 4 of 4
                        Show
                        Mapping
                        No data available
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                        Citation
                        Bai, Q., Shao, E., Ma, D., Jiao, B., Scheetz, S.D., Hartnett-Scott, K.A., Ilin, V.A., Aizenman, E., Kofler, J., Burton, E.A. (2024) A human Tau expressing zebrafish model of progressive supranuclear palsy identifies Brd4 as a regulator of microglial synaptic elimination. Nature communications. 15:81958195.