Chorein, the protein responsible for chorea-acanthocytosis, interacts with β-adducin and β-actin

Chorea-acanthocytosis (ChAc) is an autosomal, recessive hereditary disease characterized by striatal neurodegeneration and acanthocytosis, and caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene. VPS13A encodes chorein whose physiological function at the molecular level is poorly understood. In this study, we show that chorein interacts with beta-adducin and beta-actin. We first compare protein expression in human erythrocyte membranes using proteomic analysis. Protein levels of beta-adducin isoform 1 and beta-actin are markedly decreased in erythrocyte membranes from a ChAc patient. Subsequent co-immunoprecipitation (co-IP) and reverse co-IP assays using extracts from chorein-overexpressing human embryonic kidney 293 (HEK293) cells, shows that beta-adducin (isoforms I and 2) and beta-actin interact with chorein. Immunocytochemical analysis using chorein-overexpressing HEK293 cells demonstrates co-localization of chorein with beta-adducin and (beta-actin. In addition, immunoreactivity of beta-adducin isoform 1 is significantly decreased in the striatum of gene-targeted ChAc-model mice. Adducin and actin are membrane cytoskeletal proteins, involved in synaptic function. Expression of beta-adducin is restricted to the brain and hematopoietic tissues, corresponding to the main pathological lesions of ChAc, and thereby implicating beta-adducin and beta-actin in ChAc pathogenesis. (C) 2013 Elsevier Inc. All rights reserved.