Sequestration of Toxic Oligomers by HspB1 as a Cytoprotective Mechanism

Abstract

Small heat shock proteins (sHsps) are molecular chaperones that protect cells from cytotoxic effects of protein misfolding and aggregation. HspB1, an sHsp commonly associated with senile plaques in Alzheimer's disease (AD), prevents the toxic effects of A␤ aggregates in vitro. However, the mechanism of this chaperone activity is poorly understood. Here, we observed that in two distinct transgenic mouse models of AD, mouse HspB1 (Hsp25) localized to the penumbral areas of plaques. We have demonstrated that substoichiometric amounts of human HspB1 (Hsp27) abolish the toxicity of A␤ oligomers on N2a (mouse neuroblastoma) cells. Using biochemical methods, spectroscopy, light scattering, and microscopy methods, we found that HspB1 sequesters toxic A␤ oligomers and converts them into large nontoxic aggregates. HspB1 was overexpressed in N2a cells in response to treatment with A␤ oligomers. Cultured neurons from HspB1-deficient mice were more sensitive to oligomer-mediated toxicity than were those from wild-type mice. Our results suggest that sequestration of oligomers by HspB1 constitutes a novel cytoprotective mechanism of proteostasis. Whether chaperone-mediated cytoprotective sequestration of toxic aggregates may bear clues to plaque deposition and may have potential therapeutic implications must be investigated in the future.

C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity

“…7C). Previous studies have shown that extracellular sequestration of A␤ oligomers, which are considered to be the principal toxic forms of A␤ (29 -31), into larger aggregates decreases neurotoxicity (44,45). Altogether, these data suggest that C1q prevents A␤ neurotoxicity by modulating neuronal gene expression to induce a neuroprotective response that requires LRP1B and GPR6 and that LRP1B, but not GPR6, may also prevent A␤ association with neurons (Fig.…”

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

“…Recently, it has been demonstrated that, even when present at very low concentrations, molecular chaperones may inhibit the cytotoxicity of preformed misfolded oligomers formed by A, IAPP and HypF-N and fibrils formed by apolipoprotein C-II, by binding to them and converting them into larger aggregates (Ojha et al, 2011;Mannini et al, 2012, Binger et al, 2013. Interestingly, this chaperone-induced effect has been found to occur in the absence of any major structural reorganisation within the individual oligomers, which appear to maintain their overall structure and just assemble into larger species.…”

“…Indeed, the concomitant inhibition of oligomer toxicity and increased oligomer size induced by chaperones, via recruitment of more misfolded protein oligomers into the aggregates, has been interpreted to mean that chaperoneinduced clustering of oligomers is a strategy used by chaperones to inhibit oligomer toxicity (Ojha et al, 2011;Mannini et al, 2012, Binger et al, 2013Cascella et al, 2013a). By contrast, using single-molecule fluorescence techniques, it has been shown that clusterin and Bc are able to bind preformed oligomers of A and sequester them from dissociation or further growth into fibrils, revealing another possible mechanism of action of molecular chaperones which is binding in the absence of aggregate clustering (Narayan et al, 2011;Narayan et al, 2012).…”

“…In addition to these functions, chaperones have recently been found to suppress in vitro the toxic effects of protein aggregates after the aggregates have formed (Ojha et al, 2011;Mannini et al, 2012;Cascella et al, 2013a;Cascella et al, 2013b;Binger et al, 2013). In particular, it has been found for a range of systems that misfolded protein oligomers, incubated with sub-stoichiometric concentrations of chaperones in vitro, can be converted into large aggregates with substantially reduced toxicity, in the absence of any significant structural reorganisation of the individual molecules within the aggregates (Mannini et al, 2012).…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…Mitochondrial peptidases PreP and IDE are capable of degrading Aβ in the mitochondrial matrix (6). Reproduced with permission, from Muirhead et al, 2010, Biochemical Journal, 426(3), [255][256][257][258][259][260][261][262][263][264][265][266][267][268][269][270]. © The Biochemical Society [14].…”