Transgenic Dendra2::tau expression allows in vivo monitoring of tau proteostasis in Caenorhabditis elegans.
Dis Model Mech
; 17(3)2024 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-38469687
ABSTRACT
Protein homeostasis is perturbed in aging-related neurodegenerative diseases called tauopathies, which are pathologically characterized by aggregation of the microtubule-associated protein tau (encoded by the human MAPT gene). Transgenic Caenorhabditis elegans serve as a powerful model organism to study tauopathy disease mechanisms, but moderating transgenic expression level has proven problematic. To study neuronal tau proteostasis, we generated a suite of transgenic strains expressing low, medium or high levels of Dendra2tau fusion proteins by comparing integrated multicopy transgene arrays with single-copy safe-harbor locus strains generated by recombinase-mediated cassette exchange. Multicopy Dendra2tau strains exhibited expression level-dependent neuronal dysfunction that was modifiable by known genetic suppressors or an enhancer of tauopathy. Single-copy Dendra2tau strains lacked distinguishable phenotypes on their own but enabled detection of enhancer-driven neuronal dysfunction. We used multicopy Dendra2tau strains in optical pulse-chase experiments measuring tau turnover in vivo and found that Dendra2tau turned over faster than the relatively stable Dendra2. Furthermore, Dendra2tau turnover was dependent on the protein expression level and independent of co-expression with human TDP-43 (officially known as TARDBP), an aggregating protein interacting with pathological tau. We present Dendra2tau transgenic C. elegans as a novel tool for investigating molecular mechanisms of tau proteostasis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
/
Proteínas de Caenorhabditis elegans
/
Proteostase
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Dis Model Mech
Assunto da revista:
MEDICINA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Reino Unido