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

M Sancho; A E Herrera; M Orzáez; E Pérez-Payá

doi:10.1016/j.neuroscience.2013.12.062

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

Neuroscience. 2014 Mar 14:262:83-91. doi: 10.1016/j.neuroscience.2013.12.062. Epub 2014 Jan 8.

Authors

M Sancho¹, A E Herrera¹, M Orzáez², E Pérez-Payá³

Affiliations

¹ Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain.
² Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain. Electronic address: morzaez@cipf.es.
³ Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain; Instituto de Biomedicina de Valencia, IBV-CSIC, E-46010 Valencia, Spain.

PMID: 24412373
DOI: 10.1016/j.neuroscience.2013.12.062

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.

Keywords: Apaf1; Huntington’s disease; huntingtin; polyglutamines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / physiology*
Apoptotic Protease-Activating Factor 1 / antagonists & inhibitors
Apoptotic Protease-Activating Factor 1 / genetics
Apoptotic Protease-Activating Factor 1 / metabolism*
Cell Line
Cell Survival / drug effects
Cell Survival / physiology
Cells, Cultured
Corpus Striatum / drug effects
Corpus Striatum / physiology
Fibroblasts
HSP70 Heat-Shock Proteins / metabolism*
HeLa Cells
Heterocyclic Compounds / pharmacology
Humans
Huntingtin Protein
Huntington Disease / drug therapy
Huntington Disease / genetics
Huntington Disease / physiopathology
Mice
Mice, Knockout
Mice, Transgenic
Mutation
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Peptides / metabolism*
Serotonin Plasma Membrane Transport Proteins / metabolism*

Substances

Apaf1 protein, mouse
Apoptotic Protease-Activating Factor 1
HSP70 Heat-Shock Proteins
HTT protein, human
Heterocyclic Compounds
Htt protein, mouse
Huntingtin Protein
Nerve Tissue Proteins
Nuclear Proteins
Peptides
Serotonin Plasma Membrane Transport Proteins
Slc6a4 protein, mouse
polyglutamine