Nrf2-related oxidative stress response and impaired dopamine biosynthesis in a PC12 cell model of Huntingtons disease

Huntingtons disease (HD) is a devastating disease for which currently no therapy is available. It is a progressive autosomal dominant neurodegenerative disorder that is caused by a CAG repeat expansion in the HD gene, resulting in an expansion of polyglutamines at the N-terminal end of the encoded protein, designated huntingtin, and the accumulation of cytoplasmic and nuclear aggregates. Not only is there a loss of normal huntingtin function, upon expansion of the CAG repeat there is also a gain of toxic function of the huntingtin protein and this affects a wide range of cellular processes. To identify groups of genes that could play a role in the pathology of Huntingtons disease, we studied mRNA changes in an inducible PC12 model of Huntingtons disease before and after aggregates became visible. This is the first study to show the involvement Nrf2-responsive genes in the oxidative stress response in HD. Oxidative stress related transcripts were altered in expression suggesting a protective response in cells expressing mutant huntingtin at an early stage of cellular pathology. Furthermore, there was a down-regulation of catecholamine biosynthesis resulting in lower dopamine levels in culture. Our results further demonstrate an early impairment of transcription, the cytoskeleton, ion channels and receptors. Given the pathogenic impact of oxidative stress and neuroinflammation, the Nrf2-ARE signaling pathway is an attractive therapeutic target for neurodegenerative diseases.

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van Roon-Mom WM, Pepers BA, 't Hoen PA, Verwijmeren CA, den Dunnen JT, Dorsman JC, van Ommen GB