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.

Keywords: autophagy-lysosome system; chaperon-mediated autophagy; macroautophagy; protein aggregation; protein quality control; proteolysis; ubiquitin-proteasome system.

Figure 1

Protein degradation by molecular chaperones through the UPS. Molecular chaperones such as Hsp70 recognizes the hydrophobic sequences of misfolded proteins as degrons. The Ub ligase CHIP guides the chaperone-client complexes to the UPS and mediates the clients' ubiquitination. The UPS involves a cascade of E1, E2, and E3 enzymes whose cooperative activities mediate the conjugation of Ub to target proteins. In PQC, most E3s cannot recognize misfolded proteins and rather depend on molecular chaperones for substrate recognition. Ubiquitinated substrates are degraded by the proteasome into short peptides, typically with sizes of 8–12 amino acids.

Figure 2

The role of molecular chaperones in PQC. Molecular chaperones, such as Hsp70 in combination with the cochaperone Hsp40, facilitate the refolding of misfolded proteins. If the clients fail to refold, molecular chaperones can also mediate their degradation in collaboration with cellular proteolytic pathways. In principle, soluble misfolded proteins are targeted by the UPS, in which the clients are ubiquitinated by E3 Ub ligases followed by degradation through the 26S proteasome. However, if the clients are prone to aggregation or escape the surveillance of the UPS, they can be degraded by lysosomal hydrolases, either through macroautophagy or CMA. As the last step of PQC, molecular chaperones can disaggregate already formed aggregates. Also shown are misfolded proteins induced by oxidative stress in mitochondria.

Figure 3

Chaperone-mediated degradation of misfolded proteins. CMA is a selective proteolytic system in which cytosolic proteins carrying the KFERQ pentapeptide are targeted by Hsc70. The function of Hsc70 requires cochaperones, such as Hsp40, Hsp90, HIP, HOP, and BAG-1. The substrates associated with the Hsc70 chaperone system are translocated to the lysosomal membrane through the interaction of Hsc70 with LAMP2A, a single-span membrane protein. L2A, LAMP2A.