title: Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases.
abstract: OBJECTIVE
  Cells have developed quality control systems for protection against proteotoxicity. Misfolded and aggregation-prone proteins, which are behind the initiation and progression of many neurodegenerative diseases (ND), are known to challenge the proteostasis network of the cells. We aimed to explore the role of DNJ-27/ERdj5, an endoplasmic reticulum (ER)-resident thioredoxin protein required as a disulfide reductase for the degradation of misfolded proteins, in well-established Caenorhabditis elegans models of Alzheimer, Parkinson and Huntington diseases.
  
  
  RESULTS
  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 RNA interference we find an increase in the aggregation and associated pathological phenotypes (paralysis and motility impairment) caused by human β-amyloid peptide (Aβ), α-synuclein (α-syn) and polyglutamine (polyQ) proteins. In turn, DNJ-27 overexpression ameliorates these deleterious phenotypes. Surprisingly, despite being an ER-resident protein, we show that dnj-27 downregulation alters cytoplasmic protein homeostasis and causes mitochondrial fragmentation. We further demonstrate that DNJ-27 overexpression substantially protects against the mitochondrial fragmentation caused by human Aβ and α-syn peptides in these worm models.
  
  
  METHODS
  We identify C. elegans dnj-27 as a novel protective gene for the toxicity associated with the expression of human Aβ, α-syn and polyQ proteins, implying a protective role of ERdj5 in Alzheimer, Parkinson and Huntington diseases.
  
  
  CONCLUSIONS
  Our data support a scenario where the levels of DNJ-27/ERdj5 in the ER impact cytoplasmic protein homeostasis and the integrity of the mitochondrial network which might underlie its protective effects in models of proteotoxicity associated to human ND.
authors: 1 Centro Andaluz de Biología del Desarrollo (CABD-CSIC), Depto. de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide , Sevilla, Spain .
authors: Fernando
authors: F
authors: Muñoz-Lobato
authors: María Jesús
authors: MJ
authors: Rodríguez-Palero
authors: Francisco José
authors: FJ
authors: Naranjo-Galindo
authors: Freya
authors: F
authors: Shephard
authors: Christopher J
authors: CJ
authors: Gaffney
authors: Nathaniel J
authors: NJ
authors: Szewczyk
authors: Shusei
authors: S
authors: Hamamichi
authors: Kim A
authors: KA
authors: Caldwell
authors: Guy A
authors: GA
authors: Caldwell
authors: Chris D
authors: CD
authors: Link
authors: Antonio
authors: A
authors: Miranda-Vizuete
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D060746:Endoplasmic Reticulum-Associated Degradation; D015870:Gene Expression; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D059748:Proteolysis; D034622:RNA Interference; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; C471179:DNAJC10 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D010455:Peptides; D051844:alpha-Synuclein; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex
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