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.
Highlights
INTRODUCTIONMaintenance of cellular protein homeostasis (proteostasis) is crucial for cell function and survival (Powers et al, 2009; Klaips et al, 2018; Yu et al, 2019)
Maintenance of cellular protein homeostasis is crucial for cell function and survival (Powers et al, 2009; Klaips et al, 2018; Yu et al, 2019)
Of the 10 mammalian Small heat shock proteins (sHsps) proteins, HspB1, HspB5, and HspB8 are expressed in the brain, as well as, HspB6, and HspB7, albeit at lower levels (Quraishe et al, 2008)
Summary
Maintenance of cellular protein homeostasis (proteostasis) is crucial for cell function and survival (Powers et al, 2009; Klaips et al, 2018; Yu et al, 2019). Chaperones often work together in multisubunit heterocomplexes, comprised of an ATP-dependent chaperone as well as co-chaperone and accessory proteins These discrete heterocomplexes allow for specific client selection, the dynamic modulation of these clients by regulating ATPase activity, or, if a protein is unable to refold, delivery to additional proteostasis machinery for degradation or sequestration (Sahasrabudhe et al, 2017; Chen et al, 2018; Freilich et al, 2018; Grousl et al, 2018). One way for cells to address this problem is to restrict expression of sHsps until stress events (like heat shock or oxidative stress) necessitate chaperone activity Another mechanism is to sequester exposed hydrophobic regions into large, dormant, multimeric structures (sHsp oligomers); keeping sHsp chaperones poised to handle early misfolding events prior to transcription and translation of other stress-inducible chaperones (Santhanagopalan et al, 2018). Dynamic sHsp homodimers and polydisperse, homooligomeric structures regulate chaperone function as well as client protein specificity and binding
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