Work

375. TDP-43 Interacts with Cannabinoid Type 1 Receptor Modulating Its Signaling Properties

Year: 2016

Type: article

Abstract: To identify new molecular chaperones of cannabinoid type-1 receptors (CB1R), we used a proteomic approach in HEK293T cells, transfected with two spicing variants of this receptor, CB1R and CB1AR. These two isoforms differ only in the composition of the N-terminus domain. Surprisingly, the only protein found to interact differently with CB1R and CB1AR was transactive response DNA-Binding Protein 43 (TDP-43), which is known to be involved in the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The specific interactions between CB1R and TDP-43 were also confirmed by co- immunoprecipitation not only in transfected HEK293 cells, as well at the endogenous level in rat crude spinal cord. TDP-43 overexpression decreased CB1R plasma membrane levels by stimulating receptor internalization, but it did not change the total receptor levels. Further, TDP-43 enhanced CB1R ubiquitination to similar levels, as induced by the full CB1R agonist, CP 55,940. Also, overexpression of TDP-43 resulted in reduced effects of CB1R stimulation on cAMP, P-ERK1/2, and P-CREB responses. Present results revealed TDP-43 as an unexpected molecular chaperone of CB1R and these findings may have significance in the regulation of CB1R intracellular trafficking and possibly in the treatment of ALS and FTLD.

Source: Molecular Therapy

DOI: 10.1016/s1525-0016(16)33184-7