Inactivation of Apaf1 reduces the formation of mutant huntingtin-dependent aggregates and cell death

Abstract

Polyglutamine expansions in some proteins associated with neurodegenerative diseases, such as Huntington’s disease or several ataxias, lead to insoluble aggregates in the cell. These aggregates accumulate through a mechanism that is not yet fully understood, but it activates cell death pathways and contributes to kill the cell. Here, we show that apoptotic protease activating factor 1 (Apaf1) down-regulation, or treatment with pharmacological Apaf1 inhibitor SVT016426, decreases both polyglutamine-induced aggregation and polyglutamine-induced apoptotic cell death in different cellular models. We demonstrate that Apaf1 binds to both Htt and to heat shock protein chaperone Hsp70, and that this interaction is altered in the presence of the pharmacological inhibitor of Apaf1. Based on our findings, we hypothesize that Apaf1 enhances polyglutamine aggregation by reducing the cellular protein levels of available functional Hsp70.