Lithium suppresses Aβ pathology by inhibiting translation in an adult Drosophila model of Alzheimer's disease

Article


Sofola-Adesakin, Oyinkan, Castillo-Quan, Jorge I., Rallis, C., Tain, Luke S., Bjedov, Ivana, Rogers, Iain, Li, Li, Martinez, Pedro, Khericha, Mobina, Cabecinha, Melissa, Bähler, Jürg and Partridge, Linda 2014. Lithium suppresses Aβ pathology by inhibiting translation in an adult Drosophila model of Alzheimer's disease. Frontiers in Aging Neuroscience. 6 (190).
AuthorsSofola-Adesakin, Oyinkan, Castillo-Quan, Jorge I., Rallis, C., Tain, Luke S., Bjedov, Ivana, Rogers, Iain, Li, Li, Martinez, Pedro, Khericha, Mobina, Cabecinha, Melissa, Bähler, Jürg and Partridge, Linda
Abstract

The greatest risk factor for Alzheimer's disease (AD) is age, and changes in the ageing nervous system are likely contributors to AD pathology. Amyloid beta (Aβ) accumulation, which occurs as a result of the amyloidogenic processing of amyloid precursor protein (APP), is thought to initiate the pathogenesis of AD, eventually leading to neuronal cell death. Previously, we developed an adult-onset Drosophila model of AD. Mutant Aβ42 accumulation led to increased mortality and neuronal dysfunction in the adult flies. Furthermore, we showed that lithium reduced Aβ42 protein, but not mRNA, and was able to rescue Aβ42-induced toxicity. In the current study, we investigated the mechanism/s by which lithium modulates Aβ42 protein levels and Aβ42 induced toxicity in the fly model. We found that lithium caused a reduction in protein synthesis in Drosophila and hence the level of Aβ42. At both the low and high doses tested, lithium rescued the locomotory defects induced by Aβ42, but it rescued lifespan only at lower doses, suggesting that long-term, high-dose lithium treatment may have induced toxicity. Lithium also down-regulated translation in the fission yeast Schizosaccharomyces pombe associated with increased chronological lifespan. Our data highlight a role for lithium and reduced protein synthesis as potential therapeutic targets for AD pathogenesis.

JournalFrontiers in Aging Neuroscience
Journal citation6 (190)
ISSN1663-4365
Year2014
PublisherFrontiers Media
Publisher's version
License
Digital Object Identifier (DOI)doi:10.3389/fnagi.2014.00190
Web address (URL)https://doi.org/10.3389/fnagi.2014.00190
Publication dates
Online30 Jul 2014
Publication process dates
Deposited13 Feb 2018
Accepted10 Jul 2014
Accepted10 Jul 2014
Copyright information© 2014 The authors
Permalink -

https://repository.uel.ac.uk/item/8595q

  • 7
    total views
  • 44
    total downloads
  • 2
    views this month
  • 6
    downloads this month

Related outputs

The GATA transcription factor Gaf1 represses tRNA genes, inhibits growth, and extends chronological lifespan downstream of fission yeast TORC1
Rodríguez-López, M., Gonzalez, S., Hillson, O., Tunnacliffe, E., Codlin, S., Tallada, V. A., Bähler, J. and Rallis, C. The GATA transcription factor Gaf1 represses tRNA genes, inhibits growth, and extends chronological lifespan downstream of fission yeast TORC1.
Prospects of Pharmacological Interventions to Organismal Aging
Hillson, Olivia, Gonzalez, Suam and Rallis, C. 2018. Prospects of Pharmacological Interventions to Organismal Aging. Biomolecular Concepts. 9 (1), pp. 200-215.
An essential role for dNTP homeostasis following CDK-induced replication stress
Pai, Chen-Chun, Hsu, Kuo-Feng, Durley, Samuel C., Keszthelyi, Andrea, Kearsey, Stephen E., Rallis, C., Folkes, Lisa K., Deegan, Rachel, Wilkins, Sarah E., Pfister, Sophia X., De Leόn, Nagore, Schofield, Christopher J., Bähler, Jürg, Carr, Antony M. and Humphrey, Timothy C. 2019. An essential role for dNTP homeostasis following CDK-induced replication stress. Journal of Cell Science. 132 (6), p. jcs226969.
Uncovering Natural Longevity Alleles from Intercrossed Pools of Aging Fission Yeast Cells
Ellis, David A., Mustonen, Ville, Rodríguez-López, María, Rallis, C., Malecki, Michał, Jeffares, Daniel C. and Bähler, Jürg 2018. Uncovering Natural Longevity Alleles from Intercrossed Pools of Aging Fission Yeast Cells. Genetics. 210 (2), pp. 733-744.
Tbx5 is required for forelimb bud formation and continued outgrowth
Rallis, C. 2003. Tbx5 is required for forelimb bud formation and continued outgrowth. Development. 130 (12), pp. 2741-2751.
Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo
Rallis, C. 2005. Tbx3 can alter limb position along the rostrocaudal axis of the developing embryo. Development. 132 (8), pp. 1961-1970.
Integrin-Linked Kinase Is a Functional Mn2+-Dependent Protein Kinase that Regulates Glycogen Synthase Kinase-3β (GSK-3β) Phosphorylation
Wölfl, Stefan, Maydan, Mykola, McDonald, Paul C., Sanghera, Jasbinder, Yan, Jun, Rallis, C., Pinchin, Sheena, Hannigan, Gregory E., Foster, Leonard J., Ish-Horowicz, David, Walsh, Michael P. and Dedhar, Shoukat 2010. Integrin-Linked Kinase Is a Functional Mn2+-Dependent Protein Kinase that Regulates Glycogen Synthase Kinase-3β (GSK-3β) Phosphorylation. PLOS ONE. 5 (8), p. e12356.
Cell-autonomous integrin control of Wnt and Notch signalling during somitogenesis
Rallis, C., Pinchin, S. M. and Ish-Horowicz, D. 2010. Cell-autonomous integrin control of Wnt and Notch signalling during somitogenesis. Development. 137 (21), pp. 3591-3601.
Predicting the Fission Yeast Protein Interaction Network
Pancaldi, Vera, Saraç, Ömer S., Rallis, C., McLean, Janel R., Převorovský, Martin, Gould, Kathleen, Beyer, Andreas and Bähler, Jürg 2012. Predicting the Fission Yeast Protein Interaction Network. G3: Genes|Genomes|Genetics. 2 (4), pp. 453-467.
TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast
Rallis, C., Codlin, Sandra and Bähler, Jürg 2013. TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast. Aging Cell. 12 (4), pp. 563-573.
Inhibition of TORC1 signaling and increased lifespan: gained in translation?
Rallis, C. and Bähler, Jürg 2013. Inhibition of TORC1 signaling and increased lifespan: gained in translation? Aging. 5 (5), pp. 335-336.
Systematic screen for mutants resistant to TORC1 inhibition in fission yeast reveals genes involved in cellular ageing and growth
Rallis, C., Lopez-Maury, L., Georgescu, T., Pancaldi, V. and Bahler, J. 2014. Systematic screen for mutants resistant to TORC1 inhibition in fission yeast reveals genes involved in cellular ageing and growth. Biology Open. 3 (2), pp. 161-171.
LaSSO, a strategy for genome-wide mapping of intronic lariats and branch points using RNA-seq
Bitton, D. A., Rallis, C., Jeffares, D. C., Smith, G. C., Chen, Y. Y. C., Codlin, S., Marguerat, S. and Bahler, J. 2014. LaSSO, a strategy for genome-wide mapping of intronic lariats and branch points using RNA-seq. Genome Research. 24 (7), pp. 1169-1179.
Parallel Profiling of Fission Yeast Deletion Mutants for Proliferation and for Lifespan During Long-Term Quiescence
Sideri, Theodora, Rallis, C., Bitton, Danny A., Lages, Bruno M., Suo, Fang, Rodríguez-López, María, Du, Li-Lin and Bähler, Jürg 2014. Parallel Profiling of Fission Yeast Deletion Mutants for Proliferation and for Lifespan During Long-Term Quiescence. G3: Genes|Genomes|Genetics. 5 (1), pp. 145-155.
Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2, with peroxiredoxin hyperoxidation only triggered once the cellular H2O2-buffering capacity is overwhelmed
Tomalin, Lewis Elwood, Day, Alison Michelle, Underwood, Zoe Elizabeth, Smith, Graham Robert, Dalle Pezze, Piero, Rallis, C., Patel, Waseema, Dickinson, Bryan Craig, Bähler, Jürg, Brewer, Thomas Francis, Chang, Christopher Joh-Leung, Shanley, Daryl Pierson and Veal, Elizabeth Ann 2016. Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2, with peroxiredoxin hyperoxidation only triggered once the cellular H2O2-buffering capacity is overwhelmed. Free Radical Biology and Medicine. 95, pp. 333-348.
Identification of nuclear genes affecting 2-Deoxyglucose resistance inSchizosaccharomyces pombe
Vishwanatha, Akshay, Rallis, C., Bevkal Subramanyaswamy, Shubha, D'Souza, Cletus Joseph Michael, Bähler, Jürg, Schweingruber, Martin Ernst and Dawes, Ian 2016. Identification of nuclear genes affecting 2-Deoxyglucose resistance inSchizosaccharomyces pombe. FEMS Yeast Research. 16 (6), p. fow061.
Php4 Is a Key Player for Iron Economy in Meiotic and Sporulating Cells
Brault, A., Rallis, C., Normant, V., Garant, J.-M., Bahler, J. and Labbe, S. 2016. Php4 Is a Key Player for Iron Economy in Meiotic and Sporulating Cells. G3: Genes|Genomes|Genetics. 6 (10), pp. 3077-3095.
Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast
Jeffares, Daniel C., Jolly, Clemency, Hoti, Mimoza, Speed, Doug, Shaw, Liam, Rallis, C., Balloux, Francois, Dessimoz, Christophe, Bähler, Jürg and Sedlazeck, Fritz J. 2017. Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast. Nature Communications. 8, p. 14061.
Long non-coding RNA repertoire and targeting by nuclear exosome, cytoplasmic exonuclease and RNAi in fission yeast
Atkinson, Sophie, Marguerat, Samuel, Bitton, Danny, Bachand, Francois, Rodriguez-Lopez, Maria, Rallis, C., Lemay, Jean-Francois, Cotobal, Cristina, Malecki, Michal, Smialowski, Pawel, Mata, Juan, Korber, Philipp and Bahler, Jurg 2018. Long non-coding RNA repertoire and targeting by nuclear exosome, cytoplasmic exonuclease and RNAi in fission yeast. RNA. 24 (9), pp. 1195-1213.
Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes
Rallis, C., Townsend, StJohn and Bähler, Jürg 2017. Genetic interactions and functional analyses of the fission yeast gsk3 and amk2 single and double mutants defective in TORC1-dependent processes. Scientific Reports. 7, p. 44257.
The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth
Gonzalez, Suam and Rallis, C. 2017. The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth. Frontiers in Cell and Developmental Biology. 5.
Isolation of the avian homologue of the homeobox gene Mox2 and analysis of its expression pattern in developing somites and limbs
Rallis, C., Stamataki, Despina, Pontikakis, Spyros, Mankoo, Baljinder S and Karagogeos, Domna 2001. Isolation of the avian homologue of the homeobox gene Mox2 and analysis of its expression pattern in developing somites and limbs. Mechanisms of Development. 104 (1-2), pp. 121-124.
The genomic and phenotypic diversity of Schizosaccharomyces pombe
Jeffares, Daniel C, Rallis, C., Rieux, Adrien, Speed, Doug, Převorovský, Martin, Mourier, Tobias, Marsellach, Francesc X, Iqbal, Zamin, Lau, Winston, Cheng, Tammy M K, Pracana, Rodrigo, Mülleder, Michael, Lawson, Jonathan L D, Chessel, Anatole, Bala, Sendu, Hellenthal, Garrett, O'Fallon, Brendan, Keane, Thomas, Simpson, Jared T, Bischof, Leanne, Tomiczek, Bartlomiej, Bitton, Danny A, Sideri, Theodora, Codlin, Sandra, Hellberg, Josephine E E U, van Trigt, Laurent, Jeffery, Linda, Li, Juan-Juan, Atkinson, Sophie, Thodberg, Malte, Febrer, Melanie, McLay, Kirsten, Drou, Nizar, Brown, William, Hayles, Jacqueline, Salas, Rafael E Carazo, Ralser, Markus, Maniatis, Nikolas, Balding, David J, Balloux, Francois, Durbin, Richard and Bähler, Jürg 2015. The genomic and phenotypic diversity of Schizosaccharomyces pombe. Nature Genetics. 47 (3), pp. 235-241.
Cell-based screens and phenomics with fission yeast
Rallis, C. and Bähler, Jürg 2015. Cell-based screens and phenomics with fission yeast. Critical Reviews in Biochemistry and Molecular Biology. 51 (2), pp. 86-95.
RNA metabolism is the primary target of formamide in vivo
Hoyos-Manchado, Rafael, Reyes-Martín, Félix, Rallis, C., Gamero-Estévez, Enrique, Rodríguez-Gómez, Pablo, Quintero-Blanco, Juan, Bähler, Jürg, Jiménez, Juan and Tallada, Víctor A. 2017. RNA metabolism is the primary target of formamide in vivo. Scientific Reports. 7, p. Art: 15895.
Functional and regulatory profiling of energy metabolism in fission yeast
Malecki, Michal, Bitton, Danny A., Rodríguez-López, Maria, Rallis, C., Calavia, Noelia Garcia, Smith, Graeme C. and Bähler, Jürg 2016. Functional and regulatory profiling of energy metabolism in fission yeast. Genome Biology. 17 (240).
Widespread exon skipping triggers degradation by nuclear RNA surveillance in fission yeast
Bitton, Danny A., Atkinson, Sophie R., Rallis, C., Smith, Graeme C., Ellis, David A., Chen, Yuan Y.C., Malecki, Michal, Codlin, Sandra, Lemay, Jean-François, Cotobal, Cristina, Bachand, François, Marguerat, Samuel, Mata, Juan and Bähler, Jürg 2015. Widespread exon skipping triggers degradation by nuclear RNA surveillance in fission yeast. Genome Research. 25 (6), pp. 884-896.
A central role for TOR signalling in a yeast model for juvenile CLN3 disease
Bond, Michael, Brown, Rachel, Rallis, C., Bahler, Jurg and Mole, Sara 2015. A central role for TOR signalling in a yeast model for juvenile CLN3 disease. Microbial Cell. 2 (12), pp. 466-480.
Spotsizer: High-throughput quantitative analysis of microbial growth
Bischof, Leanne, Převorovský, Martin, Rallis, C., Jeffares, Daniel C., Arzhaeva, Yulia and Bähler, Jürg 2016. Spotsizer: High-throughput quantitative analysis of microbial growth. BioTechniques. 61 (4), pp. 191-201.