1. 4-Phenylbutyric acid attenuates amyloid-β proteotoxicity through activation of HSF-1 in an Alzheimer's disease model of the nematode Caenorhabditiselegans.
- Author
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Baumanns, Stefan, Muehlemeyer, Felix, Miesbauer, Laura C., Baake, Jonas, Roloff, Eva M., Beis, Daniel M., and Wenzel, Uwe
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ALZHEIMER'S disease , *CAENORHABDITIS elegans , *HEAT shock factors , *HEAT shock proteins , *RNA interference , *MEDICAL model , *HISTONE deacetylase - Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia. The pathogenesis is a complex process, in which the proteotoxicity of amyloid-β (Aβ) was identified as a major factor. 4-Phenylbutyric acid (4-PBA) is an aromatic short-chain fatty acid that may attenuate Aβ proteotoxicity through its already shown properties as a chemical chaperone or by inhibition of histone deacetylases (HDACs). In the present study, we investigated the molecular effects of 4-PBA on Aβ proteotoxicity using the nematode Caenorhabditis elegans as a model. Computer-based analysis of motility was used as a measure of Aβ proteotoxicity in the transgenic strain GMC101, expressing human Aβ 1-42 in body wall muscle cells. Aβ aggregation was quantified using the fluorescent probe NIAD-4 to correlate the effects of 4-PBA on motility with the amount of the proteotoxic protein. Furthermore, these approaches were supplemented by gene regulation via RNA interference (RNAi) to identify molecular targets of 4-PBA. 4-PBA improved the motility of GMC101 nematodes and reduced Aβ aggregation significantly. Knockdown of hsf-1 , encoding an ortholog essential for the cytosolic heat shock response, prevented the increase in motility and decrease in Aβ aggregation by 4-PBA incubation. RNAi for hda-1 , encoding an ortholog of histone deacetylase 2, also increased motility. Double RNAi for hsf-1 and hda-1 revealed a dominant effect of hsf-1 RNAi. Moreover, 4-PBA failed to further increase motility under hda-1 RNAi. Accordingly, the results suggest that 4-PBA attenuates Aβ proteotoxicity in an AD-model of C. elegans through activation of HSF-1 via inhibition of HDA-1. • Accumulation of proteotoxic amyloid-β aggregates induces an Alzheimer's disease phenotype in a Caenorhabditis elegans model. • 4-phenylbutyric acid activates heat shock factor 1, thereby reducing amyloid-β aggregation and proteotoxicity. • Inhibition of the C. elegans histone deacetylase 2 by 4-phenylbutyric acid was identified as an upstream activator of HSF-1. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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