Year: 2024
Type: article
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.
Source: Nature Chemical Biology
Institutions: University of Cambridge, UK Dementia Research Institute
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Funders: Wellcome Trust, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, UK Dementia Research Institute, Tau Consortium, Medical Research Council, NIHR Cambridge Biomedical Research Centre
Awards: G2493601830, G2537968379, G434337789, G4402799499, G4753630297, Self-propagating protein conformations as targets of intracellular immunity, Uncover mechanisms of unconventional secretion of tau using functional CRISPR screens - From basic discoveries to neurodegenerative disease therapeutics, Autophagy in health and disease.
OpenAlex ID: W4403948427