Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

Abstract

Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

Neurodegeneration and Astrogliosis in the Human CA1 Hippocampal Subfield Are Related to hsp90ab1 and bag3 in Alzheimer’s Disease

“…Evidence suggests a protective role for glia in AD, since both glial cell populations participate in the clearance of tau and Aβ (via phagocytosis or production of Aβ-degrading enzymes) [ 28 , 29 , 30 ]. In this process, the molecular chaperones Hsp70 and Hsp90 [ 31 ], and cochaperones, such as BAG3 [ 32 ], have emerged as potential regulators of tau and Aβ toxicity. However, recent studies suggest that microglia and astroglia facilitate the spread of pathological proteins and contribute to disease progression [ 33 , 34 , 35 ].…”

Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones

“…A second major activity of Hsp70 in neurodegenerative diseases is the disaggregase complex formed by HspA8, class B JDPs, and the bulky Hsp110 nucleotide exchange factors. This process has recently been carefully dissected to reveal that HspA8 alone binds to multiple sequences within amyloid aggregates. , However, class B JDPs bind to “vulnerable” stretches of these aggregates and can recruit HspA8. In addition, the Hsp110 class of NEFs are too bulky to access these JDP-HspA8 complexes and instead cycle HspA8 off the aggregate if it is not also bound to a JDP.…”

Proteotoxicity: A Fatal Consequence of Environmental Pollutants-Induced Impairments in Protein Clearance Machinery

“…A potential misfolded protein is recognized and trapped by chaperones. These chaperones alleviate the toxicity of the misfolded conformers either by sequestering them or by modulating their conformation [ 11 , 19 , 46 , 47 ]. Chaperones are potentially engaged with the folding of newly synthesized proteins, their translocation, and the refolding of unfolded client proteins.…”

“…Chaperones are potentially engaged with the folding of newly synthesized proteins, their translocation, and the refolding of unfolded client proteins. In addition to these roles, chaperones also target misfolded conformers for degradation and transfer them in spatial compartments with the help of co-chaperones [ 1 , 11 , 19 , 47 , 48 ]. These co-chaperones have a combination of the domains that function in the ubiquitin-proteasome system (UPS) and chaperone interacting domain.…”

“…To cope up with aberrant proteins, cells have several different ways to restore the integrity of a healthy proteome such as degradation via autophagy or ubiquitin-dependent proteolysis [ 7 , 8 , 9 ]. Error in the breakdown of aberrant polypeptides may result in protein aggregation which leads to pathological conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), cataracts, and diabetes [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”