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Chorein‐sensitive polymerization of cortical actin and suicidal cell death in chorea‐acanthocytosis
Author(s) -
Föller Michael,
Hermann Andreas,
Gu Shuchen,
Alesutan Ioana,
Qadri Syed M.,
Borst Oliver,
Schmidt EvaMaria,
Schiele Franziska,
Hagen Jennifer Müller vom,
Saft Carsten,
Schöls Ludger,
Lerche Holger,
Stournaras Christos,
Storch Alexander,
Lang Florian
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-198317
Subject(s) - chorea , neurodegeneration , microbiology and biotechnology , biology , programmed cell death , chemistry , apoptosis , biochemistry , pathology , medicine , disease
Chorea‐acanthocytosis is an inevitably lethal genetic disease characterized by a progressive hyperkinetic movement disorder and cognitive and behavioral abnormalities as well as acanthocytosis. The disease is caused by loss‐of‐function mutations of the gene encoding vacuolar protein sorting‐associated protein 13A ( VPS13A ) or chorein, a protein with unknown function expressed in various cell types. How chorein deficiency leads to the pathophysiology of chorea‐acanthocytosis remains enigmatic. Here we show decreased phosphoinositide‐3‐kinase (PI3K)‐p85‐subunit phosphorylation, ras‐related C3 botunlinum toxin substrate 1 (Rac1) activity, and p21 protein‐activated kinase 1 (PAK1) phosphorylation as well as depolymerized cortical actin in erythrocytes from patients with chorea‐acanthocytosis 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.—Föller, M., Hermann, A., Gu, S., Alesutan, I., Qadri, S. M., Borst, O., Schmidt, E.‐M., Schiele, F., Müller vom Hagen, J., Saft, C., Schöls, L., Lerche, H., Stournaras, C., Storch, A., Lang, F. Chorein‐sensitive polymerization of cortical actin and suicidal cell death in chorea‐acanthocytosis. FASEB J. 26, 1526–1534 (2012). www.fasebj.org