Potential Influence of Cyclo(His-Pro) on Proteostasis: Impact on Neurodegenerative Diseases

Protein function is dependent on assumption of the correct three-dimensional structure, achieved through the folding process. As a central element in ensuring cellular homeostasis, proteostasis i.e. the control of correct protein folding, trafficking and degradation, is a highly regulated process ensured by three integrated molecular pathways: i) the unfolded protein response (UPR) which is activated by the engulfment of misfolded proteins and results in protein re-folding through the expression of chaperones; ii) the ubiquitin-proteasome system (UPS) which 'flags' misfolded proteins with ubiquitin, directing them to the 26S proteasome for proteolytic degradation; iii) autophagy that, through lysosomes, removes misfolded or aggregated proteins. All three of these proteostatic controls can be impaired by the aging process and by pathological mutations highlighting the potential role of proteostasis in conditions associated with aging such as neurodegeneration, type 2 diabetes and cancer. Indeed, neurodegenerative diseases are characterised by an interconnected triumvirate of deregulated proteostasis, neuroinflammation (i.e. the uncontrolled activation of microglial cells), and oxidative stress (i.e. the unbuffered increase in reactive oxygen species). The transcription factor Nrf2, classically associated with protection against oxidative stress, can also modulate the UPR, UPS and autophagy, while inhibiting the activation of NF-kB, the key transcription factor of the inflammatory response. In this review we focus on recent data from our laboratory and others demonstrating that the protective Nrf2 pathway can be activated by the endogenous cyclic dipeptide (His-Pro), thereby driving neuroprotective effects in different pathological settings. In this context we discuss the possible utility of clyclo (His-Pro) as a promising future therapeutic option for protein misfolding disorders.