When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies

ABSTRACTIntroduction: Proteins have been historically regarded as ‘nature’s robots’: Molecular machines that are essential to cellular/extracellular physical mechanical properties and catalyze key reactions for cell/system viability. However, these robots are kept in check by other protein-based machinery to preserve proteome integrity and stability. During aging, protein homeostasis is challenged by oxidation, decreased synthesis, and increasingly inefficient mechanisms responsible for repairing or degrading damaged proteins. In addition, disruptions to protein homeostasis are hallmarks of many neurodegenerative diseases and diseases disproportionately affecting the elderly.Areas covered: Here we summarize age- and disease-related changes to the protein machinery responsible for preserving proteostasis and describe how both aging and disease can each exacerbate damage initiated by the other. We focus on alteration of proteostasis as an etiological or phenomenological factor in neurodegenerative diseases ...