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

ABSTRACT

Introduction: 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 such as Alzheimer’s, Parkinson’s, and Huntington’s, along with Down syndrome, ophthalmic pathologies, and cancer.

Expert commentary: Understanding the mechanisms of proteostasis and their dysregulation in health and disease will represent an essential breakthrough in the treatment of many (senescence-associated) pathologies. Strides in this field are currently underway and largely attributable to the introduction of high-throughput omics technologies and their combination with novel approaches to explore structural and cross-link biochemistry.

KEYWORDS:

• Proteostasis
• aging
• neurodegeneration
• metabolism
• advanced omics

Declaration of interest

Though unrelated to the contents of the manuscript, the authors disclose that A. D’Alessandro, T. Nemkov, K.C. Hansen are part of Omix Technologies, Inc. A. D’Alessandro is also an advisory board member for Hemanext, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This article was supported by funds from the Linda Crnic Institute for Down Syndrome, the 2017 Webb-Waring Biomedical Research Award sponsored by the Boettcher Foundation (both to A. D’Alessandro) and by U.S National Institutes of Health grant: NIH T32 HL007171 (to A.S. Barrett and T. Nemkov).