Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease

Blair, Laura J.; Sabbagh, Jonathan J.; Dickey, Chad A.

doi:10.1517/14728222.2014.943185

Cited by 90 publications

(83 citation statements)

References 128 publications

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“…Aggresomes, a protein complex consisting of proteasome, Ub, heat shock proteins (HSP) and γ -tubulin, serve as an alternative degrading/sequestering centre to lysosomes for many misfolded and potentially toxic cytosolic proteins [52–54]. To determine if the cytosolic pool of internalized hA is targeted to aggresomes for degradation, immunoconfocal approach was again employed.…”

Section: Resultsmentioning

confidence: 99%

Proteasome regulates turnover of toxic human amylin in pancreatic cells

Singh

Trikha

Sarkar

et al. 2016

Biochemical Journal

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Toxic human amylin (hA) oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). Although recent studies demonstrated a causal connection between hA uptake and toxicity in pancreatic cells, the mechanism of amylin’s clearance following its internalization and its relationship to toxicity is yet to be determined, and hence was investigated here. Using pancreatic rat insulinoma β-cells and human islets as model systems, we show that hA, following its internalization, first accumulates in the cytosol followed by its translocation into nucleus, and to a lesser extent lysosomes, keeping the net cytosolic amylin content low. An increase in hA accumulation in the nucleus of pancreatic cells correlated with its cytotoxicity, suggesting that its excessive accumulation in the nucleus is detrimental. hA interacted with 20S core and 19S lid subunits of the β-cell proteasomal complex, as suggested by immunoprecipitation and confocal microscopy studies, which subsequently resulted in a decrease in the proteasome’s proteolytic activity in these cells. In vitro binding and activity assays confirmed an intrinsic and potent ability of amylin to interact with the 20S core complex thereby modulating its proteolytic activity. Interestingly, less toxic and aggregation incapable rat amylin (rA) showed a comparable inhibitory effect on proteasome activity and protein ubiquitination, decoupling amylin aggregation/toxicity and amylin-induced protein stress. In agreement with these studies, inhibition of proteasomal proteolytic activity significantly increased intracellular amylin content and toxicity. Taken together, our results suggest a pivotal role of proteasomes in amylin’s turnover and detoxification in pancreatic cells.

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Section: Resultsmentioning

confidence: 99%

Proteasome regulates turnover of toxic human amylin in pancreatic cells

Singh

Trikha

Sarkar

et al. 2016

Biochemical Journal

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“…Heat‐shock protein defects have been implicated in PD (Yang et al ., 2015) and AD (Ou et al ., 2014), and HspB1 mutations are associated with familial motor neuron diseases (Muranova et al ., 2015). Hsp90 and its co‐chaperones regulate tau and Aβ processing (Blair et al ., 2014), and Hsp90 may specifically protect TDP‐43 from ROS‐induced aggregation (Chang et al ., 2013a). The mitochondrial HSP70, also called ‘stress‐70’ or ‘mortalin’, is implicated in PD and in vitro longevity (Wadhwa et al ., 2015).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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“…Overexpression of WT a-Syn did not induce oligomer formation and toxicity in 5Y cells as observed with A53T a-Syn overexpression, suggesting that formation of oligomers was important for triggering the toxicity of a-Syn. Inhibiting Hsp90 leads to compensatory induction of HSPs and has been proposed as an effective strategy for the therapy of neurodegenerative diseases (Luo et al, 2010;Blair et al, 2014). In fact, because of their ability to induce Hsp70, several Hsp90 inhibitors have recently been tested in a rat a-Syn PD model (Putcha et al, 2010;McFarland et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

A Novel Hsp90 Inhibitor Activates Compensatory Heat Shock Protein Responses and Autophagy and Alleviates Mutant A53Tα-Synuclein Toxicity

et al. 2015

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A potential cause of neurodegenerative diseases, including Parkinson's disease (PD), is protein misfolding and aggregation that in turn leads to neurotoxicity. Targeting Hsp90 is an attractive strategy to halt neurodegenerative diseases, and benzoquinone ansamycin (BQA) Hsp90 inhibitors such as geldanamycin (GA) and 17-(allylamino)-17-demethoxygeldanamycin have been shown to be beneficial in mutant A53T a-synuclein PD models. However, current BQA inhibitors result in off-target toxicities via redox cycling and/or arylation of nucleophiles at the C19 position. We developed novel 19-substituted BQA (19BQA) as a means to prevent arylation. In this study, our data demonstrated that 19-phenyl-GA, a lead 19BQA in the GA series, was redox stable and exhibited little toxicity relative to its parent quinone GA in human dopaminergic SH-SY5Y cells as examined by oxygen consumption, trypan blue, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), and apoptosis assays. Meanwhile, 19-phenyl-GA retained the ability to induce autophagy and potentially protective heat shock proteins (HSPs) such as Hsp70 and Hsp27. We found that transduction of A53T, but not wild type (WT) a-synuclein, induced toxicity in SH-SY5Y cells. 19-Phenyl-GA decreased oligomer formation and toxicity of A53T a-synuclein in transduced cells. Mechanistic studies indicated that mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase signaling was activated by A53T but not WT a-synuclein, and 19-phenyl-GA decreased mTOR activation that may be associated with A53T a-synuclein toxicity. In summary, our results indicate that 19BQAs such as 19-phenyl-GA may provide a means to modulate protein-handling systems including HSPs and autophagy, thereby reducing the aggregation and toxicity of proteins such as mutant A53T a-synuclein.

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Targeting Hsp90 and its co-chaperones to treat Alzheimer’s disease

Cited by 90 publications

References 128 publications

Proteasome regulates turnover of toxic human amylin in pancreatic cells

Proteasome regulates turnover of toxic human amylin in pancreatic cells

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

A Novel Hsp90 Inhibitor Activates Compensatory Heat Shock Protein Responses and Autophagy and Alleviates Mutant A53Tα-Synuclein Toxicity

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