4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor

Mimori, Seisuke; Ohtaka, Hiroyasu; Koshikawa, Yukari; Kawada, Koichi; Kaneko, Masayuki; Okuma, Yasunobu; Nomura, Yasuyuki; Murakami, Yasuoki; Hamana, Hiroshi

doi:10.1016/j.bmcl.2013.08.001

Cited by 59 publications

(49 citation statements)

References 21 publications

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“…However, our results suggested that 4-PBA mainly acts as a chemical chaperone rather than as HDAC inhibitors as 4-PBA did not alter SP-A protein expression in this study. This is also consistent with the findings of Mimori et al, who have shown that 4-PBA is neuroprotective as a chemical chaperone rather than as an HDAC inhibitor (Mimori et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

“…Moreover, 4-PBA also possesses histone deacetylase (HDAC)-inhibitor activity. HDAC inhibitors were originally designed as anti-cancer agents because of their important roles in the epigenetic regulation of protein translation (Mimori et al, 2013). The HDAC inhibitory function of 4-PBA has been studied in many orphan neurodegenerative diseases related to abnormal histone acetylation, such as Huntington's disease and amyotrophic lateral sclerosis (Gardian et al, 2005;Ryu et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Mutations of rat surfactant protein A have distinct effects on its glycosylation, secretion, aggregation and degradation

et al. 2014

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Mutations of rat surfactant protein A have distinct effects on its glycosylation, secretion, aggregation and degradation

et al. 2014

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“…The pathway that begins with disrupted protein folding and ends with protein aggregation in embryonic cells subjected to (56) and is used to ameliorate protein folding-associated diseases (57). These observations suggest that targeting the protein-folding crisis is a potential interventional approach to prevent diabetes-associated birth defects.…”

Section: Discussionmentioning

confidence: 99%

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Zhao

Cao

Reece

2017

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes mellitus in early pregnancy increases the risk in infants of birth defects, such as neural tube defects (NTDs), known as diabetic embryopathy. NTDs are associated with hyperglycemia-induced protein misfolding and Caspase-8–induced programmed cell death. The present study shows that misfolded proteins are ubiquitinylated, suggesting that ubiquitin-proteasomal degradation is impaired. Misfolded proteins form aggregates containing ubiquitin-binding protein p62, suggesting that autophagic-lysosomal clearance is insufficient. Additionally, these aggregates contain the neurodegenerative disease-associated proteins α-Synuclein, Parkin, and Huntingtin (Htt). Aggregation of Htt may lead to formation of a death-inducing signaling complex of Hip1, Hippi, and Caspase-8. Treatment with chemical chaperones, such as sodium 4-phenylbutyrate (PBA), reduces protein aggregation in neural stem cells in vitro and in embryos in vivo. Furthermore, treatment with PBA in vivo decreases NTD rate in the embryos of diabetic mice, as well as Caspase-8 activation and cell death. Enhancing protein folding could be a potential interventional approach to preventing embryonic malformations in diabetic pregnancies.

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“…We showed that 4-PBA protects against neuronal cell death by primarily acting as a chemical chaperone rather than as an HDAC inhibitor using three simple 4-(p-substituted phenyl) butyric acids [44]. 4-(4-Aminophenyl) butanoic acid (4-APB) exhibited high affinity an HDAC7/4-PBA-derivative binding model.…”

Section: Development Of 4-pba In Our Researchmentioning

confidence: 99%

Neuroprotective Effects of 4-phenylbutyric Acid and Its Derivatives: Possible Therapeutics for Neurodegenerative Diseases

Mimori¹,

Hosoi²,

Kaneko³

et al. 2017

JHS

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Abstract:The pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases involves the aggregation of denatured and misfolded nascent proteins. Consequently, many pharmacological approaches have been developed to prevent protein aggregation. 4-Phenylbutyric acid (4-PBA) is a chemical chaperone that shows potential as a candidate drug for the treatment of neurodegenerative diseases. The main actions of chemical chaperones are the amelioration of unfolded proteins and the suppression of their aggregation, which result in protective effects against endoplasmic reticulum stress-induced neuronal cell death. Furthermore, 4-PBA exhibits inhibitory activity against histone deacetylases (HDACs). However, owing to the problematically high doses of 4-PBA currently required for therapeutic efficacy, the optimization of 4-PBA is crucial for its effective medicinal application. In the present review, we summarize the recent advances in research on the basic actions of 4-PBA and its derivatives. We also discuss whether these compounds could be viable therapeutic agents against neurodegenerative diseases.

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4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor

Cited by 59 publications

References 21 publications

Mutations of rat surfactant protein A have distinct effects on its glycosylation, secretion, aggregation and degradation

Mutations of rat surfactant protein A have distinct effects on its glycosylation, secretion, aggregation and degradation

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Neuroprotective Effects of 4-phenylbutyric Acid and Its Derivatives: Possible Therapeutics for Neurodegenerative Diseases

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