SOD1G93A Induces a Unique PSAP-Dependent Mitochondrial Apoptosis Pathway via Bax–Bak Interaction

Abstract

Amyotrophic lateral syndrome (ALS) is a progressive degenerative disorder characterized by motor neuron death and axon degeneration. Mitochondrial dysfunction plays a key role in the pathogenesis of ALS, the mechanism of which remains poorly understood. The B-cell lymphoma-2 (Bcl-2) family of proteins that control and mediate mitochondrial function and apoptosis, including the pro-apoptotic members Bcl2-Associated X (Bax), are involved in ALS development. The death receptor 6 (DR6) regulates motor neuron death in ALS, and DR6 antibodies can prevent axon degeneration and motor neuron damage by blocking DR6. Previous studies demonstrated that PSAP localized to mitochondria and was required for DR6-induced apoptosis. In this study, SOD1G93A was transfected into the motor neuron cell line NSC-34 to serve as an ALS cell model in vitro. The data assessed the role of PSAP in SOD1G93A-induced apoptosis and demonstrated that the overexpression of SOD1G93A, but not wtSOD1, induced PARP cleavage, caspase-3 activation, cytochrome c release, and Bax translocation. PSAP, Bax, and Bak were necessary for SOD1G93A-induced apoptosis, as silencing PSAP inhibited SOD1G93A-mediated cell death that was dependent on Bax–Bak interaction.