Protein Quality Control by Molecular Chaperones in Neurodegeneration

Abstract

Protein homeostasis (proteostasis) requires the timely degradation of misfolded proteins and their aggregates by protein quality control (PQC), of which molecular chaperones are an essential component. Compared with other cell types, PQC in neurons is particularly challenging because they have a unique cellular structure with long extensions. Making it worse, neurons are postmitotic, i.e., cannot dilute toxic substances by division, and, thus, are highly sensitive to misfolded proteins, especially as they age. Failure in PQC is often associated with neurodegenerative diseases, such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), and prion disease. In fact, many neurodegenerative diseases are considered to be protein misfolding disorders. To prevent the accumulation of disease-causing aggregates, neurons utilize a repertoire of chaperones that recognize misfolded proteins through exposed hydrophobic surfaces and assist their refolding. If such an effort fails, chaperones can facilitate the degradation of terminally misfolded proteins through either the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). If soluble, the substrates associated with chaperones, such as Hsp70, are ubiquitinated by Ub ligases and degraded through the proteasome complex. Some misfolded proteins carrying the KFERQ motif are recognized by the chaperone Hsc70 and delivered to the lysosomal lumen through a process called, chaperone-mediated autophagy (CMA). Aggregation-prone misfolded proteins that remain unprocessed are directed to macroautophagy in which cargoes are collected by adaptors, such as p62/SQSTM-1/Sequestosome-1, and delivered to the autophagosome for lysosomal degradation. The aggregates that have survived all these refolding/degradative processes can still be directly dissolved, i.e., disaggregated by chaperones. Studies have shown that molecular chaperones alleviate the pathogenic symptoms by neurodegeneration-causing protein aggregates. Chaperone-inducing drugs and anti-aggregation drugs are actively exploited for beneficial effects on symptoms of disease. Here, we discuss how chaperones protect misfolded proteins from aggregation and mediate the degradation of terminally misfolded proteins in collaboration with cellular degradative machinery. The topics also include therapeutic approaches to improve the expression and turnover of molecular chaperones and to develop anti-aggregation drugs.

Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1

“…Several genes involved in familial forms of neurodegenerative disorders exert key functions in the autophagy pathway. These notably comprise PRKN, PINK1 and SQSTM1 (99)(100)(101)(102). In the recent years, major works provided evidence that, in neurons and immune cells, functional defects in such genes hamper mitophagy (a specialized form of autophagy), stimulate the inflammasome pathway and foster the presentation of mitochondrial antigens by MHC class I molecules (33,103,104).…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…116 Inhibitors of the proteasome and several anti-inflammatory agents cause the redistribution of targeted proteins in organelles. 116,126 The inhibition of proteasome induces transcription of p62 via transcription factor nuclear factor erythroid-related factor 1 (NRF1). 116,126 The inhibition of proteasome induces transcription of p62 via transcription factor nuclear factor erythroid-related factor 1 (NRF1).…”

“…125 Some protein aggregates inhibit proteasome function but trigger lysosomal protein degradation through a number of mechanisms. 116,126 The inhibition of proteasome induces transcription of p62 via transcription factor nuclear factor erythroid-related factor 1 (NRF1). 127 p62, also known as Sequestosome 1 (SQSTM1), is a ubiquitin-binding adaptor protein that bridges the proteasome-dependent degradation process to autophagy.…”

Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases

“…The UPS is responsible for the degradation of most proteins, and any negative perturbation of the degradation process can have a deleterious effect on general protein quality control. This is particularly detrimental to neurons because they cannot dilute toxic aggregates by mitotic cell division [4]. The UPS enzymatic cascade consists of two discrete and successive steps: first the covalent tagging of the substrate protein by a poly-ubiquitin chain; second, the subsequent degradation of the tagged protein by the 26S proteasome [5].…”