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
-
- Cell Cycle Proteins
- Humans
- Disease Models, Animal*
- Transcription Factors*/genetics
- Transcription Factors*/metabolism
- tau Proteins*/genetics
- tau Proteins*/metabolism
- Neurons/metabolism
- Supranuclear Palsy, Progressive*/genetics
- Supranuclear Palsy, Progressive*/metabolism
- Supranuclear Palsy, Progressive*/pathology
- Azepines/pharmacology
- Zebrafish*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Phagocytosis
- Triazoles/pharmacology
- Animals, Genetically Modified*
- Brain/metabolism
- Brain/pathology
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Rats
- Synapses*/metabolism
- Microglia*/metabolism
- Microglia*/pathology
- Bromodomain Containing Proteins
- Animals
- PubMed
- 39294122 Full text @ Nat. Commun.
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping