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Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Inhibition of Autophagy Potentiated Hippocampal Cell Death Induced by Endoplasmic Reticulum Stress and its Activation by Trehalose Failed to be Neuroprotective

Author(s): Luisa Halbe and Abdelhaq Rami*

Volume 16, Issue 1, 2019

Page: [3 - 11] Pages: 9

DOI: 10.2174/1567202616666190131155834

Price: $65

Abstract

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate.

Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability.

Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

Keywords: Autophagy, HT22 neurons, ER stress, trehalose, cell death, lysosomes.

[1]
Schröder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem 2005; 74: 739-89.
[2]
Frakes AE, Dillin A. The UPRER. sensor and coordinator of organismal homeostasis. Mol Cell 2017; 66(6): 761-71.
[3]
Fujita E, Kouroku Y, Isoai A, et al. Two Endoplasmic Reticulum-Associated Degradation (ERAD) systems for the novel variant of the mutant dysferlin. Ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet 2007; 16(6): 618-29.
[4]
Yorimitsu T, Klionsky DJ. Endoplasmic reticulum stress. A new pathway to induce autophagy. Autophagy 2007; 3(2): 160-2.
[5]
Ogata M, Hino S, Saito A, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 2006; 26(24): 9220-31.
[6]
Yoshimori T. Autophagy: A regulated bulk degradation process inside cells. Biochem Biophys Res Commun 2004; 313(2): 453-8.
[7]
Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000; 19(21): 5720-8.
[8]
Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000; 290(5497): 1717-21.
[9]
Glick D, Barth S, Macleod KF. Autophagy: Cellular and molecular mechanisms. J Pathol 2010; 221(1): 3-12.
[10]
Galluzzi L, Vicencio JM, Kepp O, Tasdemir E, Maiuri MC, Kroemer G. To die or not to die: That is the autophagic question. Curr Mol Med 2008; 8(2): 78-91.
[11]
Levine B, Klionsky DJ. Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6(4): 463-77.
[12]
Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4(2): 151-75.
[13]
Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta 2013; 1833(12): 3448-59.
[14]
Rami A, Kögel D. Apoptosis meets autophagy-like cell death in the ischemic penumbra. Two sides of the same coin? Autophagy 2008; 4(4): 422-6.
[15]
Rami A. Autophagy in neurodegeneration: Firefighter and/or incendiarist? Neuropathol Appl Neurobiol 2009; 35(5): 449-61.
[16]
Yorimitsu T, Nair U, Yang Z, Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem 2006; 281(40): 30299-304.
[17]
Rani V, Deshmukh R, Jaswal P, Kumar P, Bariwal J. Alzheimer's disease. Is this a brain specific diabetic condition? Physiol Behav 2016; 164(ptA). : 259-67.
[18]
Mizushima N, Yoshimori T. How to interpret LC3 immunoblotting. Autophagy 2007; 3(6): 542-5.
[19]
Martindale JJ, Fernandez R, Thuerauf D, et al. Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circ Res 2006; 98(9): 1186-93.
[20]
Liu S, Sarkar C, Dinizo M, et al. Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death Dis 2015; 6: e1582.
[21]
Iwata A, Christianson JC, Bucci M, et al. Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci USA 2005; 102(37): 13135-40.
[22]
Ravikumar B, Berger Z, Vacher C, O’Kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 2006; 15(7): 1209-16.
[23]
Steiger-Barraissoul S, Rami A. Serum deprivation induced autophagy and predominantly an AIF-dependent apoptosis in hippocampal HT22 neurons. Apoptosis 2009; 14(11): 1274-88.
[24]
Fekadu J, Rami A. Beclin-1 deficiency alters autophagosome formation, lysosome biogenesis and enhances neuronal vulnerability of HT22 hippocampal cells. Mol Neurobiol 2016; 53(8): 5500-9.
[25]
Koike M, Shibata M, Tadakoshi M, et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 172(2): 454-69.
[26]
Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006; 441(7095): 885-9.
[27]
Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441(7095): 880-4.
[28]
Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 2008; 32(3): 329-39.
[29]
Martinez-Vicente M. Autophagy in neurodegenerative diseases. From pathogenic dysfunction to therapeutic modulation. Semin Cell Dev Biol 2015; 40: 115-26.
[30]
Sarkar S, Rubinsztein DC. Small molecule enhancers of autophagy for neurodegenerative diseases. Mol Biosyst 2008; 4(9): 895-901.
[31]
Sarkar S, Rubinsztein DC. Huntington’s disease: Degradation of mutant huntingtin by autophagy. FEBS J 2008; 275(17): 4263-70.
[32]
Vidal RL, Matus S, Bargsted L, Hetz C. Targeting autophagy in neurodegenerative diseases. Trends Pharmacol Sci 2014; 35(11): 583-91.
[33]
Portbury SD, Hare DJ, Sgambelloni C, et al. Trehalose improves cognition in the transgenic Tg2576 mouse model of Alzheimer’s disease. J Alzheimers Dis 2017; 60(2): 549-60.
[34]
Castillo K, Nassif M, Valenzuela V, et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 2013; 9(9): 1308-20.
[35]
Mardones P, Rubinsztein DC, Hetz C. Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport. Sci Signal 2016; 9(416): fs2.
[36]
Li Y, Guo Y, Wang X, et al. Trehalose decreases mutant SOD1 expression and alleviates motor deficiency in early but not end-stage amyotrophic lateral sclerosis in a SOD1-G93A mouse model. Neuroscience 2015; 298: 12-25.
[37]
Li Y, Luo Y, Luo T, et al. Trehalose inhibits protein aggregation caused by transient ischemic insults through preservation of proteasome activity, not via induction of autophagy. Mol Neurobiol 2017; 54(9): 6857-69.
[38]
Tanji K, Miki Y, Maruyama A, et al. Trehalose intake induces chaperone molecules along with autophagy in a mouse model of Lewy body disease. Biochem Biophys Res Commun 2015; 465(4): 746-52.
[39]
Redmann M, Wani WY, Volpicelli-Daley L, Darley-Usmar V, Zhang J. Trehalose does not improve neuronal survival on exposure to alpha-synuclein pre-formed fibrils. Redox Biol 2017; 11: 429-37.

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