DJ-1 modulates aggregation and pathogenesis in models of Huntington's disease

Abstract

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.

Using Drosophila models of Huntington's disease as a translatable tool

“…Other candidates from screens that have yet to be tested in mammalian systems are TCF, a protein involved in Wnt signaling, rpi, a metabolic enzyme, TDO, a member of the M a n u s c r i p t 13 kynurenine pathway, Tra1, a component of the HAT complex, and DJ-1α, an oxidationsensitive chaperone protein (Campesan et al, 2011;Dupont et al, 2012;Sajjad et al, 2014;Wang et al, 2012;Zhang et al, 2010). Considering the successful translation of many other candidates discovered or validated in Drosophila models of HD (Table 2), these remain prime candidates for evaluation in mammalian systems.…”

The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration

“…Therefore, we used a Drosophila model of HD, in which flies pan-neuronally express a mutant HTT exon 1 fragment (HTT93Q) and exhibit a progressive loss of photoreceptor neurons (rhabdomeres) during their lifespan. [34][35][36][37][38] Treatment of adult HD flies with either mometasone or GRT10 markedly rescued mutant HTT-mediated neurodegeneration, although the extent of protection with GRT10 was slightly lower than with mometasone (Figures 3c and d). Moreover, treatment of the glucocorticoids during larval stages reduced neurodegeneration in newly emerged (day 0) HD flies (Figure 3e), suggesting that the transrepression arm of glucocorticoid signaling is neuroprotective both in adult HD flies and during development.…”

DJ-1/PARK7: A New Therapeutic Target for Neurodegenerative Disorders

“…Sajjad et al showed the chaperone activity of DJ-1 in resolving the abnormal aggregation of mHTT. 25) 2.4. Protein Degradation DJ-1 has been reported to be involved in proteolytic pathways, such as the ubiquitin proteasome system and autophagy lysosome system.…”