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Chemical induction of Hsp70 reduces ?-synuclein aggregation in neuroglioma cells.

ABSTRACT: Misfolding and aggregation of ?-synuclein (?-syn) is associated with the development of a number of neurodegenerative diseases including Parkinson's disease (PD). Analyses of post mortem tissues revealed the presence of molecular chaperones within ?-syn aggregates, suggesting that chaperones play a role in ?-syn misfolding and aggregation. In fact, inhibition of chaperone activity aggravates ?-syn toxicity, and the overexpression of chaperones, particularly 70-kDa heat shock protein (Hsp70), protects against ?-syn-induced toxicity. In this study, we investigated the effect of carbenoxolone (CBX), a glycyrrhizic acid derivative previously reported to upregulate Hsp70, in human neuroglioma cells overexpressing ?-syn. We report that CBX treatment lowers ?-syn aggregation and prevents ?-syn-induced cytotoxicity. We demonstrate further that Hsp70 induction by CBX arises from activation of heat shock factor 1 (HSF1). The Hsp70 inhibitor MAL3-101 and the Hsp70 enhancer 115-7c led to an increase or decrease in ?-syn aggregation, respectively, in agreement with these findings. In summary, this study provides a proof-of-principle demonstration that chemical modulation of the Hsp70 machine is a promising strategy to prevent ?-syn aggregation.

SUBMITTER: Kilpatrick K

PROVIDER: S-EPMC4532326 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Chemical induction of Hsp70 reduces α-synuclein aggregation in neuroglioma cells.

Kilpatrick Kiri K Novoa Jose Andres JA Hancock Tommy T Guerriero Christopher J CJ Wipf Peter P Brodsky Jeffrey L JL Segatori Laura L

ACS chemical biology 20130501 7

Misfolding and aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases including Parkinson's disease (PD). Analyses of post mortem tissues revealed the presence of molecular chaperones within α-syn aggregates, suggesting that chaperones play a role in α-syn misfolding and aggregation. In fact, inhibition of chaperone activity aggravates α-syn toxicity, and the overexpression of chaperones, particularly 70-kDa heat shock protein (Hsp70), pro ...[more]

PMID: 23594135

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Project description:BACKGROUND:Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins. METHODS:Mice expressing high levels of mutant forms of tau and ?-synuclein (?Syn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation. RESULTS:Mice expressing low levels of G85R-SOD1:YFP, alone, lived normal lifespans and were free of evidence of inclusion pathology, setting the stage to use this protein as a reporter of proteostatic function. We observed robust induction of G85R-SOD1:YFP inclusion pathology in the neuropil of spinal cord and brainstem of bigenic mice that co-express high levels of mutant tau in the spinal axis and develop robust spinal tau pathology (JNPL3 mice). In contrast, in crosses of the G85R-SOD1:YFP mice with mice that model spinal ?-synucleinopathy (the M83 model of ?Syn pathology), we observed no G85R-SOD1:YFP inclusion formation. Similarly, in crosses of the G85R-SOD1:YFP mice to mice that model cortical tau pathology (rTg4510 mice), we did not observe induction of G85R-SOD1:YFP inclusions. CONCLUSION:Despite robust burdens of neurodegenerative pathology in M83 and rTg4510 mice, the introduction of the G85R-SOD1:YFP protein was induced to aggregate only in the context of spinal tau pathology present in the JNPL3 model. These findings suggest unexpected specificity, mediated by both the primary protein pathology and cellular context, in the induced "secondary aggregation" of a mutant form of SOD1 that could be viewed as a reporter of proteostatic function.

Dataset Information

Chemical induction of Hsp70 reduces ?-synuclein aggregation in neuroglioma cells.

Publications

Chemical induction of Hsp70 reduces α-synuclein aggregation in neuroglioma cells.

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