Endoplasmic Reticulum Enrollment in Alzheimer’s Disease

Viana, Ricardo J.S.; Nunes, Ana V. M.; Rodrigues, Cecília M. P.

doi:10.1007/s12035-012-8301-x

Cited by 71 publications

(46 citation statements)

References 137 publications

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“…Not shown in this figure is the dimerization of some of these proteins. Under conditions of severe proteotoxic stress or loss of homeostasis, proteins may not undergo degradation or refolding and are sequestered in fibrillar deposits, such as Lewy bodies in Parkinson's disease Viana et al 2012). Proteotoxic stress in the endoplasmic reticulum may therefore trigger a biphasic response, with pro-survival UPR and ERAD responses predominating with mild injury, but UPR-initiated apoptosis predominating with severe injury.…”

Section: Heat Shock Protein Classification and Functionmentioning

confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

141

119

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Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stressinduced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

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Section: Heat Shock Protein Classification and Functionmentioning

confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

141

119

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“…Excessive and prolonged stresses ultimately lead to inflammation and apoptosis (Fribley et al, 2009;Jäger et al, 2012;Sovolyova et al, 2014). In addition, previous studies have suggested that ER stress is involved in many diseases, including neurodegenerative diseases (Katayama et al, 2004;Lindholm et al, 2006;Homma et al, 2009;Salminen et al, 2009;Doyle et al, 2011;Malhi and Kaufman, 2011;Cornejo and Hetz, 2013;Omura et al, 2013;Viana et al, 2012). Interestingly, previous reports found that METH could mediate ER stress via the PERK, ATF6, and IRE1 pathways of both neuronal and glial cells [12,16].…”

Section: Introductionmentioning

confidence: 99%

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

et al. 2017

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-Methamphetamine (METH) is a neurotoxic drug that causes brain damage by inducing neuronal and glial cell death together with glial cell hyperactivity-mediated progressive neurodegeneration. Previous studies have shown that METH induced glial cell hyperactivity and death via oxidative stress, the inflammatory response, and endoplasmic reticulum stress (ER stress) mechanisms, and melatonin could reverse these effects. However, the exact mechanism of the protective role of melatonin in METH-mediated ER stress has not been understood. This study investigated the protective effect of melatonin against METH toxicity-mediated ER stress in glial cells. Our study demonstrated that METH increased glial cell toxicity related to METH-induced ER stress by stimulating the unfolded protein response (UPR) to activate the expression of ER stress transducers, including phosphorylated doublestranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), activating transcription factor (ATF6), and phosphorylated inositol-requiring enzyme 1 (p-IRE1). Moreover, the expression of binding immunoglobulin protein (Bip), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, phosphorylated eukaryotic translation initiation factor 2 alpha (p-eIF2α) and spliced X-box-binding protein-1 (XBP-1) mRNA were also increased. Melatonin reduced ER stress induced by METH toxicity by reducing the expression of ER stress response genes and proteins in a concentration-dependent manner. In addition, melatonin promoted the expression of Bip chaperone in a concentration-dependent manner. Taken together, our findings suggest that melatonin can protect against ER stress-induced glial cell death induced by METH.

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“…44 Under severe ER stress, ATF4, XBP1s, and ATF6 can increase the expression of the pro-apoptotic transcription factor DDIT3. 19 We found that expression Eif2ak3, Atf6, Atf4, Xbp1s, Ddit3, and Atg5 mRNAs was significantly increased in the livers showing AApoAII deposition. The expression of Eif2ak3, Atf4, Xbp1s, and Atg5 mRNAs was significantly increased in kidneys in which AApoAII was deposited.…”

Section: Discussionmentioning

confidence: 65%

“…21,22,24 Although it is unclear how extracellular Ab sends signals to the ER, it has been shown that extracellular Ab can induce the UPR. 19,38,39 AApoAII amyloid fibrils deposit in extracellular spaces, but it remains unclear whether monomers, oligomers, or fibrils accumulate intracellularly. HSPA5 does not localize exclusively to the ER and under specific circumstances, such as development of drug resistance and cell transformation, it has been shown to relocate to the cell membrane.…”

Section: Discussionmentioning

confidence: 99%

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Extracellular deposition of mouse senile AApoAII amyloid fibrils induced different unfolded protein responses in the liver, kidney, and heart

Luo

Sawashita

Tian

et al. 2015

Laboratory Investigation

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Mouse senile amyloidosis is a disorder in which apolipoprotein A-II deposits extracellularly in many organs as amyloid fibrils (AApoAII). In this study, we intravenously injected 1 mg of isolated AApoAII fibrils into R1.P1-Apoa2 c mice, to induce AApoAII amyloidosis. We observed that the unfolded protein response was induced by deposition of AApoAII amyloid. We found that the mRNA and the protein expression levels of heat shock protein A5 (HSPA5; also known as glucoseregulated protein 78) were increased in the liver with AApoAII amyloid deposits. Immunohistochemistry showed that HSPA5 was only detected in hepatocytes close to AApoAII amyloid deposits. Furthermore, gene transcription of several endoplasmic reticulum (ER) stress-related proteins increased, including eukaryotic translation initiation factor 2 alpha kinase 3 (Eif2ak3), activating transcription factor 6 (Atf6), activating transcription factor 4 (Atf4), X-box-binding protein 1 splicing (Xbp1s), DNA-damage inducible transcript 3 (Ddit3), and autophagy protein 5 (Atg5). Moreover, apoptosis-positive cells were increased in the liver. Similar results were seen in the kidney but not in the heart. Our study indicates that ER stress responses differed among tissues with extracellular AApoAII amyloid fibril deposition. Although upregulated HSPA5 and the activated unfolded protein response might have roles in protecting tissues against aggregated extracellular AApoAII amyloid deposition, prolonged ER stress induced apoptosis in the liver and the kidney.

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Endoplasmic Reticulum Enrollment in Alzheimer’s Disease

Cited by 71 publications

References 137 publications

Heat shock proteins in neurodegenerative disorders and aging

Heat shock proteins in neurodegenerative disorders and aging

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

Extracellular deposition of mouse senile AApoAII amyloid fibrils induced different unfolded protein responses in the liver, kidney, and heart

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