Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

Abstract

Maintaining the proteome to preserve the health of an organism in the face of developmental changes, environmental insults, infectious diseases, and rigors of aging is a formidable task. The challenge is magnified by the inheritance of mutations that render individual proteins subject to misfolding and/or aggregation. Maintenance of the proteome requires the orchestration of protein synthesis, folding, degradation, and trafficking by highly conserved/deeply integrated cellular networks. In humans, no less than 2000 genes are involved. Stress sensors detect the misfolding and aggregation of proteins in specific organelles and respond by activating stress-responsive signaling pathways. These culminate in transcriptional and posttranscriptional programs that up-regulate the homeostatic mechanisms unique to that organelle. Proteostasis is also strongly influenced by the general properties of protein folding that are intrinsic to every proteome. These include the kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We then introduce chemical approaches to prevent the misfolding or aggregation of specific proteins through direct binding interactions. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organismal proteostasis.

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

“…Slowing down translation rates can significantly improve protein folding, therefore contributing to reestablishment of homeostasis in these diseases (67)(68)(69). Drugs such as Salubrinal (11) and Guanabenz (13) or Sephin 1 (70), which were described as selective inhibitors of cellular complexes that dephosphorylate eIF2α, have been considered toward that purpose and showed promising results in animals.…”

Firefly luciferase mutants as sensors of proteome stress

“…Since the proteostasis network encompasses a wide range of key proteins involved in different steps in protein biogenesis, maintenance (folding and refolding), trafficking and degradation, both activators and inhibitors have been screened to affect each of these individual steps. A combination of chemical and biological approaches can be used to rebalance the cellular proteostasis capacity under stress conditions and therefore hold a great therapeutic potential to treat several human diseases including protein conformational disorders and cancer (Lindquist and Kelly, 2011;Mu et al, 2008;Powers et al, 2009). …”

Transcellular chaperone signaling: an organismal strategy for integrated cell stress responses

“…This is primarily controlled by the master regulator of the HSR, which in eukaryotes is heat shock transcription factor HSF-1. HSF-1 functions as a rheostat for acute stress, to prevent cell death, and monitors chronic proteotoxic stress that affects fecundity and lifespan (Abravaya et al, 1991;Morley and Morimoto, 2004;Åkerfelt et al, 2010;Lindquist and Kelly, 2011;McMullen et al, 2012). HSF-1 is a highly conserved member of the HSF gene family that is constitutively expressed and negatively regulated in most cell types in the absence of stress (Åkerfelt et al, 2010).…”