Abstract
BackgroundAll living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein (hsp) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity.MethodsWe exposed wild type and selected hsp mutant worms to Mn (30 min) and next evaluated further the most susceptible strains. We analyzed survival, protein carbonylation (as a marker of oxidative stress) and Parkinson’s disease related gene expression immediately after Mn exposure. Lastly, we observed dopaminergic neurons in wild type worms and in hsp-70 mutants following Mn treatment. Analysis of the data was performed by one-way or two way ANOVA, depending on the case, followed by post-hoc Bonferroni test if the overall p value was less than 0.05.ResultsWe verified that the loss of hsp-70, hsp-3 and chn-1 increased the vulnerability to Mn, as exposed mutant worms showed lower survival rate and increased protein oxidation. The importance of hsp-70 against Mn toxicity was then corroborated in dopaminergic neurons, where Mn neurotoxicity was aggravated. The lack of hsp-70 also blocked the transcriptional upregulation of pink1, a gene that has been linked to Parkinson’s disease.ConclusionsTaken together, our data suggest that Mn exposure modulates heat shock protein expression, particularly HSP-70, in C. elegans. Furthermore, loss of hsp-70 increases protein oxidation and dopaminergic neuronal degeneration following manganese exposure, which is associated with the inhibition of pink1 increased expression, thus potentially exacerbating the vulnerability to this metal.
Highlights
All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example
Lethality of the transgenic strains lacking hsp-4, hsp-43, hsf1 and hsp-12.6 were indistinguishable from wild type worms, hsp-70 mutants exhibited hypersensitivity to Mninduced lethality (LD50 = 73.08 mM) compared to N2 worms (LD50 = 46.13 mM) (Fig. 1a, p < 0.05)
Loss of pink-1 is associated with mitochondrial impairments, oxidative stress, and DAergic neuronal loss, as DA neurons may be Conclusions Taken together, our data suggest that Mn exposure modulates heat shock protein (HSP) expression, HSP-70, in C. elegans
Summary
All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Molecular chaperones are highly evolutionarily conserved and ubiquitously found in subcellular compartments, cells, and tissues, being essential for the stability of the proteome under normal and stressful conditions [1]. The expression of many molecular chaperones is regulated by environmental and physiological stresses that can interfere with folding stability, leading to a flux of misfolded proteins [2]. Thereby, metals themselves are able to generate aberrant interactions with proteins such as beta-amyloid, α synuclein and prion proteins [5, 6]. As a consequence, exposed subjects may develop a syndrome known as manganism, where alterations in movement, speech and face expression may appear [14,15,16]
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