Chorea-acanthocytosis is an inevitably lethal genetic disease characterized by a progressive hyperkinetic movement disorder, cognitive and behavioural abnormalities as well as acanthocytosis. The disease is caused by loss-of-function mutations ofVPS13Agene encoding chorein, a protein with unknown function expressed in various cell types. How chorein deficiency leads to the pathophysiology of chorea-acanthocytosis remained enigmatic. Here, we show decreased PI3K-p85-subunit phosphorylation, Rac1 activity and PAK1 phosphorylation as well as depolymerised cortical actin in erythrocytes from chorea-acanthocytosis patients and in K562-erythrocytic cells following chorein silencing. Pharmacological inhibition of PI3K, Rac1 or PAK1 similarly triggered actin depolymerization. Moreover, in K562 cells both chorein silencing and PAK1 inhibition with IPA-3 decreased phosphorylation of Bad, a Bcl2-associated protein promoting apoptosis by forming mitochondrial pores, followed by mitochondrial depolarization, DNA fragmentation and phosphatidylserine exposure at the cell surface, all hallmarks of apoptosis. Our observations reveal chorein as a novel powerful regulator of cytoskeletal architecture and cell survival thus explaining erythrocyte misshape and possibly neurodegeneration in chorea-acanthocytosis.