Midnolin, a Genetic Risk Factor for Parkinson's Disease, Promotes Neurite Outgrowth Accompanied by Early Growth Response 1 Activation in PC12 Cells.
Mol Cell Biol
; : 1-12, 2024 Sep 12.
Article
en En
| MEDLINE
| ID: mdl-39264361
ABSTRACT
Parkinson's disease (PD) is an age-related progressive neurodegenerative disease. Previously, we identified midnolin (MIDN) as a genetic risk factor for PD. Although MIDN copy number loss increases the risk of PD, the molecular function of MIDN remains unclear. To investigate the role of MIDN in PD, we established monoclonal Midn knockout (KO) PC12 cell models. Midn KO inhibited neurite outgrowth and neurofilament light chain (Nefl) gene expression. Although MIDN is mainly localized in the nucleus, it does not encode DNA-binding domains. We therefore hypothesized that MIDN might bind to certain transcription factors and regulate gene expression. Of the candidate transcription factors, we focused on early growth response 1 (EGR1) because it is required for neurite outgrowth and its target genes are downregulated by Midn KO. An interaction between MIDN and EGR1 was confirmed by immunoprecipitation. Surprisingly, although EGR1 protein levels were significantly increased in Midn KO cells, the binding of EGR1 to the Nefl promoter and resulting transcriptional activity were downregulated as measured by luciferase assay and chromatin immunoprecipitation quantitative real-time polymerase chain reaction. Overall, we identified the MIDN-dependent regulation of EGR1 function. This mechanism may be an underlying reason for the neurite outgrowth defects of Midn KO PC12 cells.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Mol Cell Biol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Japón
Pais de publicación:
Estados Unidos