FOXP1 is a Transcription Factor for the Alzheimer's Disease Risk Gene SORL1

Abstract

Sortilin-related receptor 1 (SORL1) is a risk gene of Alzheimer's disease (AD), and some protein-truncating (PTV) and rare missense variants causing the loss of function of SORL1 contribute to AD pathogenesis. SORL1 is an endosomal receptor that interacts with multiple protein sorting complexes to facilitate the transport of various cargoes through the endolysosomal network (ELN). However, the regulatory mechanisms governing SORL1 expression remain unknown. Through biochemical methods, we identified Forkhead Box P1 (FOXP1) as a binding protein to the minimal promoter region of SORL1 gene. Silencing FOXP1 using siRNA significantly decreased the activity of the SORL1 minimal promoter and reduced SORL1 protein and mRNA levels in the neuroblastoma cell line SH-SY5Y. Additionally, using 5xFAD mouse models of AD, we observed significantly decreased FOXP1 and SORL1 expression in neurons within the prefrontal cortex. Disruption of ELN and the autophagy degradation system by bafilomycin A1 (BafA1) appeared to be a specific condition to suppress FOXP1 and hence SORL1 in SH-SY5Y cells. These findings highlight the critical role of FOXP1 in regulating SORL1 expression and suggest that FOXP1 could be a potential target to maintain SORL1 expression for AD prevention and therapy.