Casein Kinase 1δ Phosphorylates TDP-43 and Suppresses Its Function in Tau mRNA Processing.
J Alzheimers Dis
; 91(4): 1527-1539, 2023.
Article
em En
| MEDLINE
| ID: mdl-36641675
ABSTRACT
BACKGROUND:
Neurofibrillary tangle aggregated from anomalous hyperphosphorylated tau is a hallmark of Alzheimer's disease (AD). Trans-active response DNA-binding protein of 43 kDa (TDP-43) enhances the instability and exon (E) 10 inclusion of tau mRNA. Cytoplasmic inclusion of hyperphosphorylated TDP-43 in the neurons constitutes the third most prevalent proteinopathy of AD. Casein kinase 1δ (CK1δ) is elevated in AD brain and phosphorylates TDP-43 in vitro.OBJECTIVE:
To determine the roles of CK1δ in phosphorylation, aggregation, and function of TDP-43 in the processing of tau mRNA.METHODS:
The interaction and colocalization of TDP-43 and CK1δ were analyzed by co-immunoprecipitation and immunofluorescence staining. TDP-43 phosphorylation by CK1δ was determined in vitro and in cultured cells. RIPA-insoluble TDP-43 aggregates obtained by ultracentrifugation were analyzed by immunoblots. The instability and E10 splicing of tau mRNA were studied by using a reporter of green fluorescence protein tailed with 3'-untranslational region of tau mRNA and a mini-tau gene and analyzed by real-time quantitative PCR and reverse transcriptional PCR.RESULTS:
We found that CK1δ interacted and co-localized with TDP-43. TDP-43 was phosphorylated by CK1δ at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells, which was mutually enhanced. CK1δ overexpression promoted the aggregation of TDP-43 and suppressed its activity in enhancing the instability and E10 inclusion of tau mRNA.CONCLUSION:
CK1δ phosphorylates TDP-43, promotes its aggregation, and inhibits its activity in promoting the instability of tau mRNA and inclusion of tau E10. Elevated CK1δ in AD brain may contribute to TDP-43 and tau pathologies directly or indirectly.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
/
Caseína Quinase Idelta
/
Proteínas de Ligação a DNA
Limite:
Humans
Idioma:
En
Revista:
J Alzheimers Dis
Assunto da revista:
GERIATRIA
/
NEUROLOGIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China