DJ-1 modulates aggregation and pathogenesis in models of Huntington's disease.
The oxidation-sensitive chaperone protein DJ-1 has been implicated in several human disorders including cancer and neurodegenerative diseases. During neurodegeneration associated with protein misfolding, such as that observed in Alzheimer's disease and Huntington's disease (HD), both oxidative stress and protein chaperones have been shown to modulate disease pathways. Therefore, we set out to investigate whether DJ-1 plays a role in HD. We found that DJ-1 expression and its oxidation state are abnormally increased in the human HD brain, as well as in mouse and cell models of HD. Furthermore, overexpression of DJ-1 conferred protection in vivo against neurodegeneration in yeast and Drosophila. Importantly, the DJ-1 protein directly interacted with an expanded fragment of huntingtin Exon 1 (httEx1) in test tube experiments and in cell models and accelerated polyglutamine aggregation and toxicity in an oxidation-sensitive manner. Our findings clearly establish DJ-1 as a potential therapeutic target for HD and provide the basis for further studies into the role of DJ-1 in protein misfolding diseases.
Neuroscience Group, Centre for Biological Sciences, University of Southampton, Basset Crescent East, Southampton, UK.
Muhammad U
MU
Sajjad
Edward W
EW
Green
Leonor
L
Miller-Fleming
Sarah
S
Hands
Federico
F
Herrera
Susanna
S
Campesan
Ali
A
Khoshnan
Tiago F
TF
Outeiro
Flaviano
F
Giorgini
Andreas
A
Wyttenbach
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010455:Peptides / Q000378:metabolism; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D015003:Yeasts / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D010455:Peptides; C097188:polyglutamine; D054464:Peroxiredoxins; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1