Phenylbutyric Acid Rescues Endoplasmic Reticulum Stress-Induced Suppression of APP Proteolysis and Prevents Apoptosis in Neuronal Cells

Department of Comparative Medicine, University of Washington, Seattle, Washington, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2010; 5(2):e9135. DOI: 10.1371/journal.pone.0009135
Source: PubMed


The familial and sporadic forms of Alzheimer's disease (AD) have an identical pathology with a severe disparity in the time of onset [1]. The pathological similarity suggests that epigenetic processes may phenocopy the Familial Alzheimer's disease (FAD) mutations within sporadic AD. Numerous groups have demonstrated that FAD mutations in presenilin result in ‘loss of function’ of γ-secretase mediated APP cleavage [2], [3], [4], [5]. Accordingly, ER stress is prominent within the pathologically impacted brain regions in AD patients [6] and is reported to inhibit APP trafficking through the secretory pathway [7], [8]. As the maturation of APP and the cleaving secretases requires trafficking through the secretory pathway [9], [10], [11], we hypothesized that ER stress may block trafficking requisite for normal levels of APP cleavage and that the small molecular chaperone 4-phenylbutyrate (PBA) may rescue the proteolytic deficit.

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    • "Events associated with ER-stress have been linked to the pathogenesis of Alzheimer's disease, which is characterized by the accumulation of amyloid-derived products. In fact, rescue the ER-stress-induced suppression of amyloid precursor protein has been shown to be one of the beneficial actions of PBA, thereby preventing apoptosis in neuroblastoma NAG cells [36]. Interestingly, the intracellular domain of the amyloid precursor protein (AICD) enhances the sensitivity of human SHEP neuroblastoma cells to apoptosis induced by tunicamycin [37]. "
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    ABSTRACT: Understanding how neural cells handle proteostasis stress in the endoplasmic reticulum (ER) is important to decipher the mechanisms that underlie the cell death associated with neurodegenerative diseases and to design appropriate therapeutic tools. Here we have compared the sensitivity of a human neuroblastoma cell line (SH-SY5H) to the ER stress caused by an inhibitor of protein glycosylation with that observed in human embryonic kidney (HEK-293T) cells. In response to stress, SH-SY5H cells increase the expression of mRNA encoding downstream effectors of ER stress sensors and transcription factors related to the unfolded protein response (the spliced X-box binding protein 1, CCAAT-enhancer-binding protein homologous protein, endoplasmic reticulum-localized DnaJ homologue 4 and asparagine synthetase). Tunicamycin-induced death of SH-SY5H cells was prevented by terminal aromatic substituted butyric or valeric acids, in association with a decrease in the mRNA expression of stress-related factors, and in the accumulation of the ATF4 protein. Interestingly, this decrease in ATF4 protein occurs without modifying the phosphorylation of the translation initiation factor eIF2α. Together, these results show that when short chain phenyl acyl acids alleviate ER stress in SH-SY5H cells their survival is enhanced.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "This limited instead of complete protection is likely due to the fact that PBA acts as a chemical chaperone that assists in folding malfolded or unfolded proteins. PBA however does not prevent events that damage the ER membrane or affect the ER calcium channels (Ozcan et al., 2006; Wiley et al., 2010). A similar result, partial and temporary protection against TBTO, was found in our previous study for the calcium chelator BAPTA (Katika et al., 2011). "
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    ABSTRACT: Bis (tri-n-butyltin) oxide (TBTO) is one of the organotin compounds known to induce immunosuppression. Previously, we examined the effect of TBTO on whole-genome mRNA expression in the human T lymphocyte cell line Jurkat, which led to the hypothesis that induction of endoplasmic reticulum (ER) stress is the first initiated event, which induces a rise of intracellular calcium levels, activation of NF-kB and NFAT, T cell activation response and oxidative stress together finally resulting in apoptosis. The present study verified this hypothesis with biochemical and cytological experiments. The induction of ER stress was confirmed by the rapid raise in protein levels of ATF3 and DDIT3. Moreover, the impairment of cell viability by TBTO was moderated by the ER stress inhibitor phenyl butyric acid. Real-time fluorescence microscopy confirmed that TBTO increases intracellular calcium levels within 2min of exposure. Furthermore, the involvement of increased calcium levels in the effects of TBTO was evident from the induction of three calcium-dependent events: (1) activation of the protease activity of M-calpain, (2) induction of NF-kB (p65) expression, and (3) activation of NFAT. The induction of oxidative stress was verified by detection of increased levels of reactive oxygen species and a decrease in amount of reduced glutathione. We also showed that TBTO induces cleavage of caspase-3, an event known to mediate apoptosis. Finally, comparative microarray data analysis showed that many of the processes observed in vitro also occur in vivo in thymuses of TBTO-treated mice.
    Full-text · Article · May 2012 · Toxicology Letters
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    • "Several groups have shown beneficial effects upon AD pathology and memory performance with no signs of toxicity in AD transgenic mouse models (84, 91–94). Further, phenylbutyrate specifically represses apoptosis in stressed neuronal systems (95–97). Findings have indicated that the beneficial effects of phenylbutyrate (increased synaptic plasticity, improved learning and memory and attenuation of spatial memory deficits) may be attributed to restored acetylation of histone H4 and to the clearance of intraneuronal Aβ accumulation (91, 92). "
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    ABSTRACT: Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.
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