Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases

Abstract

Modulation of endogenous cellular defense mechanisms via the vitagene system represents an innovative approach to therapeutic intervention in diseases causing chronic tissue damage, such as in neurodegeneration. The possibility of high-throughoutput screening using proteomic techniques, particularly redox proteomics, provide more comprehensive overview of the interaction of proteins, as well as the interplay among processes involved in neuroprotection. Here by introducing the hormetic dose response concept, the mechanistic foundations and applications to the field of neuroprotection, we discuss the emerging role of heat shock protein as prominent member of vitagene network in neuroprotection and redox proteomics as a tool for investigating redox modulation of stress responsive vitagenes. Hormetic mechanisms are reviewed as possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the neurodegenerative disease process.

Keywords: Alzheimer’s disease; Bilirubin; Heat shock proteins; Heme oxygenase; Neurodegenerative disorders; Oxidative stress; Vitagenes.

Fig. 1

Vitagenes and the pathway of cellular stress response. Proteotoxic stresses causing accumulation of misfolded proteins trigger the cellular stress response. HSPs that are normally bound to HSF1 are titrate away by damaged proteins with resulting HSF-1 activation. Multi-step activation of HSF1 involves post-translational modifications, such as hyperphosphorylation, deacetylation or sumoylation, which allow HSF1 to trimerize, translocate into the nucleus, and bind to heat-shock elements (HSEs) in the promoter regions of its target hsp genes. Nutritional antioxidants, are able to activate vitagenes, such as heme oxygenase, Hsp70, thioredoxin reductase and sirtuins which represent an integrated system for cellular stress tolerance. Activation of Vitagene system, with up-regulation of HO-1, Thioredoxin, GSH and Sirtuin, results in reduction of pro-oxidant conditions. During inflammaging, including aged-associated pathologies a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage, leading to degeneration and cell death of critical parenchymal cells. Phytochemicals and acetylcarnitine act through the activation of transcription factor Nrf2, which after binding to the antioxidant responsive element up-regulates vitagenes

Fig. 2

Heme metabolism and HO-1 enzyme activity. HO-1 catalyze the rate-limiting step in heme metabolism. Heme is cleaved by HO-1 to yield equimolar quantities of iron, CO, and biliverdin. The regulatory actions of CO can be, at least in part mediated, by the activation of MAPK pathway. Biliverdin is converted to bilirubin by biliverdin reductase, this latter being also endowed with Ser/Thr/Tyr kinase activity through which regulates cell growth and metabolism. At low physiological concentrations, bilirubin behaves as a powerful antioxidant

Fig. 3

Dose–response curve depicting the quantitative features of hormesis