A gene‐targeted mouse model for chorea‐acanthocytosis

Abstract

Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, CHAC shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis. Recently, we identified the gene, CHAC, encoding a novel protein, chorein, in which a deletion mutation was found in Japanese families with CHAC. In the present study, we have identified the mouse CHAC cDNA sequence and the exon-intron structures of the gene and produced a CHAC model mouse introducing no. 60-61 exon deletion corresponding to a human disease mutation by a genetargeting technique. The mice began to show acanthocytosis and motor disturbance in old age. In behavioral observations, locomotor activity was significantly decreased and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determinations, the dopamine metabolite, homovanillic acid, concentration decreased significantly in the portion including the midbrain of the mutant mice. These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset. The CHAC model mouse therefore provides a good model system to study the human disease.

Chorein Sensitivity of Actin Polymerization, Cell Shape and Mechanical Stiffness of Vascular Endothelial Cells

“…Clinically overt disease develops at an age between 30 and 70 years and progresses to disability and premature death [10]. The lack of chorein action in ChAc leads to disappearance of cortical actin filaments in erythrocytes and thus to the spectacular erythrocyte shape change of acanthocytosis [3,11]. Chorein is further expressed and modifies actin polymerization in blood platelets [12].…”

Vacuolar Protein Sorting Protein 13A, TtVPS13A, Localizes to the Tetrahymena thermophila Phagosome Membrane and Is Required for Efficient Phagocytosis

“…Mutations in the human VPS13B gene also result in an autosomal recessive disorder, Cohen syndrome, with neurological symptoms (22). Finally, mice with a mutation in the homologue of human VPS13A have been generated, mimicking some features of ChAc, particularly in old age (44).…”

Chorein Sensitive Arrangement of Cytoskeletal Architecture

“…In erythrocytes from ChAc patients the lack of chorein leads to almost complete disappearance of the cortical actin filaments network and thus to the spectacular erythrocyte shape change of acanthocytosis [1,16]. Chorein is further expressed in K562 cells [1], blood platelets [17], human umbilical vein endothelial cells (HUVECs) [18] and some tumor cells [5].…”

“…The analysis was performed in cells isolated from chorea-acanthocytosis patients expressing defective chorein levels. The cell types chosen were erythrocytes, which are known to virtually lack cortical actin and are highly deformed [1,16], and fibroblasts, which could be cultured ex vivo following isolation from patients and healthy volunteers and are considered a particularly appropriate cell type for the detailed study of cytoskeletal reorganization and signaling [33,34,35]. Our findings provide evidence that chorein deficiency influences the organization of all three cytoskeletal structures, implying a role of this protein in the maintenance of cytoskeleton integrity.…”