Small Heat Shock Proteins, Big Impact on Protein Aggregation in Neurodegenerative Disease

Abstract

Misfolding, aggregation, and aberrant accumulation of proteins are central components in the progression of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates. In disease states, molecular chaperones can display protective or aberrant effects, including the promotion and stabilization of toxic protein aggregates. This seems to be dependent on the aggregating protein and discrete chaperone interaction. Small heat shock proteins (sHsps) are a class of molecular chaperones that typically associate early with misfolded proteins. These interactions hold proteins in a reversible state that helps facilitate refolding or degradation by other chaperones and co-factors. These sHsp interactions require dynamic oligomerization state changes in response to diverse cellular triggers and, unlike later steps in the chaperone cascade of events, are ATP-independent. Here, we review evidence for modulation of neurodegenerative disease-relevant protein aggregation by sHsps. This includes data supporting direct physical interactions and potential roles of sHsps in the stewardship of pathological protein aggregates in brain. A greater understanding of the mechanisms of sHsp chaperone activity may help in the development of novel therapeutic strategies to modulate the aggregation of pathological, amyloidogenic proteins. sHsps-targeting strategies including modulators of expression or post-translational modification of endogenous sHsps, small molecules targeted to sHsp domains, and delivery of engineered molecular chaperones, are also discussed.

Alzheimer cells on their way to derailment show selective changes in protein quality control network

“…They act early-stage on hydrophobic stretches of their substrates, possibly upstream of the ATPdependent Hsp70-Hsp90 chaperone cascade (Bakthisaran et al, 2015;Haslbeck and Vierling, 2015;McHaourab et al, 2009;Morán Luengo et al, 2019;Zwirowski et al, 2017). Out of 10 mammalian sHSPs, five family members are expressed in neurons and play a role in neurodegenerative diseases: HSPB1, HSPB5, HSPB8 and, to a lower extend, HSPB6 (Quraishe et al, 2008;Webster et al, 2019). HSPB1 and HSPB6 both show a strong increase in all brain regions (Fig.…”

Role of Mitochondrial Stress Protein HSP60 in Diabetes-Induced Neuroinflammation

“…It is evident that hyperglycemia-induced alternations in mitochondrial electron transport are a key causative factor for mitochondrial dysfunction [34]. Molecular stress proteins are a group of proteins which enable mitochondria to respond to stressinduced protein misfolding [35]. Heat shock protein 60 (HSP60) is one such molecular stress protein that is expressed in both prokaryotes and eukaryotic cells [36].…”

Effect of Arginine on Chaperone-Like Activity of HspB6 and Monomeric 14-3-3ζ

“…However, cells have protective mechanisms that allow them to minimize the risk of protein aggregation [7,8]. Small heat shock proteins (sHsps) belong to the family of molecular chaperones and protect cells against different kind of stresses, serving as a first line of defense in preventing protein aggregation [9][10][11]. One of the most important functions of sHsps is to prevent protein aggregation by binding of non-native or misfolded protein molecules and hold them in a folding-competent conformation.…”