PUBLICATION
Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion
- Authors
- Lopez, A., Siddiqi, F.H., Villeneuve, J., Ureshino, R.P., Jeon, H.Y., Koulousakis, P., Keeling, S., McEwan, W.A., Fleming, A., Rubinsztein, D.C.
- ID
- ZDB-PUB-241101-11
- Date
- 2024
- Source
- Nature Chemical Biology : (Journal)
- Registered Authors
- Fleming, Angeleen
- Keywords
- none
- MeSH Terms
-
- Carbonic Anhydrases/metabolism
- Humans
- Tauopathies*/drug therapy
- Tauopathies*/metabolism
- Tauopathies*/pathology
- Animals, Genetically Modified
- Carbonic Anhydrase Inhibitors*/chemistry
- Carbonic Anhydrase Inhibitors*/pharmacology
- Disease Models, Animal
- Exocytosis/drug effects
- Lysosomes/drug effects
- Lysosomes/metabolism
- Animals
- Zebrafish*
- Methazolamide/pharmacology
- tau Proteins*/metabolism
- Mice
- PubMed
- 39482469 Full text @ Nat. Chem. Biol.
Citation
Lopez, A., Siddiqi, F.H., Villeneuve, J., Ureshino, R.P., Jeon, H.Y., Koulousakis, P., Keeling, S., McEwan, W.A., Fleming, A., Rubinsztein, D.C. (2024) Carbonic anhydrase inhibition ameliorates tau toxicity via enhanced tau secretion. Nature Chemical Biology. :.
Abstract
Tauopathies are neurodegenerative diseases that manifest with intracellular accumulation and aggregation of tau protein. These include Pick's disease, progressive supranuclear palsy, corticobasal degeneration and argyrophilic grain disease, where tau is believed to be the primary disease driver, as well as secondary tauopathies, such as Alzheimer's disease. There is a need to develop effective pharmacological therapies. Here we tested >1,400 clinically approved compounds using transgenic zebrafish tauopathy models. This revealed that carbonic anhydrase (CA) inhibitors protected against tau toxicity. CRISPR experiments confirmed that CA depletion mimicked the effects of these drugs. CA inhibition promoted faster clearance of human tau by promoting lysosomal exocytosis. Importantly, methazolamide, a CA inhibitor used in the clinic, also reduced total and phosphorylated tau levels, increased neuronal survival and ameliorated neurodegeneration in mouse tauopathy models at concentrations similar to those seen in people. These data underscore the feasibility of in vivo drug screens using zebrafish models and suggest serious consideration of CA inhibitors for treating tauopathies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping