Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of neurodegenerative diseases

Resumen del trabajo presentado al 4th Spanish Worm Meeting, celebrado en Carmona (Sevilla) del 14 al 15 de marzo de 2013.-- et al.Cells have developed quality control systems for protecting against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of neurodegenerative diseases such as Alzheimer, Parkinson or Huntington, are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an ER-resident protein required as a disulfide reductase for the degradation of misfolded proteins, in well-established Caenorhabditis elegans models of these neurodegenerative diseases. We demonstrate that DNJ-27 is an ER luminal protein and that its expression is induced upon ER stress via IRE-1/XBP-1. When dnj-27 expression is downregulated by RNAi we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human ß-amyloid peptide, α-synuclein and polyglutamine proteins. In turn, dnj-27 overexpression ameliorates these deleterious phenotypes. This protection is also achieved, to some extent, when ERdj5 (the dnj-27 mammalian orthologue) is expressed in these C. elegans models of neurodegenerative diseases. Surprisingly, despite being an ER-resident protein, we show that dnj-27 downregulation causes mitochondrial fragmentation and enhanced cytoplasmic protein degradation. Together, we identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human ß-amyloid peptide, α-synuclein and polyglutamine proteins, implying a potential protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases. Our data support a scenario where the levels of DNJ-27/ERdj5 in the endoplasmic reticulum impact cytoplasmic protein homeostasis and underlies its protection in models of cytoplasmic proteotoxicity associated to neurodegenerative diseases.Peer Reviewe