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Gospodinova KO, Olsen D, Kaas M, et al. Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks. Cell Mol Neurobiol. 2021;doi: 10.1007/s10571-021-01163-7.
Gospodinova, K. O., Olsen, D., Kaas, M., Anderson, S. M., Phillips, J., Walker, R. M., Bermingham, M. L., Payne, A. L., Giannopoulos, P., Pandya, D., Spires-Jones, T. L., Abbott, C. M., Porteous, D. J., Glerup, S., & Evans, K. L. (2021). Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks. Cellular and molecular neurobiology, . https://doi.org/10.1007/s10571-021-01163-7
Gospodinova, Katerina O, et al. "Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks." Cellular and molecular neurobiology vol. (2021). doi: https://doi.org/10.1007/s10571-021-01163-7
Gospodinova KO, Olsen D, Kaas M, Anderson SM, Phillips J, Walker RM, Bermingham ML, Payne AL, Giannopoulos P, Pandya D, Spires-Jones TL, Abbott CM, Porteous DJ, Glerup S, Evans KL. Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks. Cell Mol Neurobiol. 2021 Nov 06; doi: 10.1007/s10571-021-01163-7. Epub 2021 Nov 06. PMID: 34741697.
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Cell Mol Neurobiol. 2021 Nov 06; doi: 10.1007/s10571-021-01163-7. Epub 2021 Nov 06.

Loss of SORCS2 is Associated with Neuronal DNA Double-Strand Breaks.

Cellular and molecular neurobiology

Katerina O Gospodinova, Ditte Olsen, Mathias Kaas, Susan M Anderson, Jonathan Phillips, Rosie M Walker, Mairead L Bermingham, Abigail L Payne, Panagiotis Giannopoulos, Divya Pandya, Tara L Spires-Jones, Catherine M Abbott, David J Porteous, Simon Glerup, Kathryn L Evans

Affiliations

  1. Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  2. Department of Biomedicine, Aarhus University, 8000, Aarhus, Denmark.
  3. University of Edinburgh, Chancellor's Building, 49, Edinburgh, EH16 4SB, UK.
  4. Centre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, EH8 9XD, UK.
  5. Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU, UK. [email protected].

PMID: 34741697 DOI: 10.1007/s10571-021-01163-7

Abstract

SORCS2 is one of five proteins that constitute the Vps10p-domain receptor family. Members of this family play important roles in cellular processes linked to neuronal survival, differentiation and function. Genetic and functional studies implicate SORCS2 in cognitive function, as well as in neurodegenerative and psychiatric disorders. DNA damage and DNA repair deficits are linked to ageing and neurodegeneration, and transient neuronal DNA double-strand breaks (DSBs) also occur as a result of neuronal activity. Here, we report a novel role for SORCS2 in DSB formation. We show that SorCS2 loss is associated with elevated DSB levels in the mouse dentate gyrus and that knocking out SORCS2 in a human neuronal cell line increased Topoisomerase IIβ-dependent DSB formation and reduced neuronal viability. Neuronal stimulation had no impact on levels of DNA breaks in vitro, suggesting that the observed differences may not be the result of aberrant neuronal activity in these cells. Our findings are consistent with studies linking the VPS10 receptors and DNA damage to neurodegenerative conditions.

© 2021. The Author(s).

Keywords: DNA double-strand breaks; Neurodegeneration; Neuronal activity; SORCS2

References

  1. Adamec E, Vonsattel JP, Nixon RA (1999) DNA strand breaks in Alzheimer’s disease. Brain Res 849:67–77. https://doi.org/10.1016/s0006-8993(99)02004-1 - PubMed
  2. Alemany S, Ribasés M, Vilor-Tejedor N et al (2015) New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder. Am J Med Genet B, Neuropsychiatr Genet 168:459–470. https://doi.org/10.1002/ajmg.b.32341 - PubMed
  3. Crowe SL, Movsesyan VA, Jorgensen TJ, Kondratyev A (2006) Rapid phosphorylation of histone H2A.X following ionotropic glutamate receptor activation. Eur J Neurosci 23:2351–2361. https://doi.org/10.1111/j.1460-9568.2006.04768.x - PubMed
  4. Davies G, Lam M, Harris SE et al (2018) Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun 9:2098. https://doi.org/10.1038/s41467-018-04362-x - PubMed
  5. Deinhardt K, Kim T, Spellman DS et al (2011) Neuronal growth cone retraction relies on proneurotrophin receptor signaling through Rac. Sci Signal 4:ra82. https://doi.org/10.1126/scisignal.2002060 - PubMed
  6. Duncan L, Yilmaz Z, Gaspar H et al (2017) Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa. Am J Psychiatry 174:850–858. https://doi.org/10.1176/appi.ajp.2017.16121402 - PubMed
  7. Fabbri C, Serretti A (2016) Genetics of long-term treatment outcome in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 65:17–24. https://doi.org/10.1016/j.pnpbp.2015.08.008 - PubMed
  8. Fabbri C, Tansey KE, Perlis RH et al (2018) New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation. Pharmacogenomics J 18:413–421. https://doi.org/10.1038/tpj.2017.44 - PubMed
  9. Fasci D, van Ingen H, Scheltema RA, Heck AJR (2018) Histone interaction landscapes visualized by crosslinking mass spectrometry in intact cell nuclei. Mol Cell Proteomics 17:2018–2033. https://doi.org/10.1074/mcp.RA118.000924 - PubMed
  10. Firsanov DV, Solovjeva LV, Svetlova MP (2011) H2AX phosphorylation at the sites of DNA double-strand breaks in cultivated mammalian cells and tissues. Clin Epigenet 2:283–297. https://doi.org/10.1007/s13148-011-0044-4 - PubMed
  11. Glerup S, Nykjaer A, Vaegter CB (2014a) Sortilins in neurotrophic factor signaling. Handb Exp Pharmacol 220:165–189. https://doi.org/10.1007/978-3-642-45106-5_7 - PubMed
  12. Glerup S, Olsen D, Vaegter CB et al (2014b) SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia. Neuron 82:1074–1087. https://doi.org/10.1016/j.neuron.2014.04.022 - PubMed
  13. Glerup S, Bolcho U, Mølgaard S et al (2016) SorCS2 is required for BDNF-dependent plasticity in the hippocampus. Mol Psychiatry 21:1740–1751. https://doi.org/10.1038/mp.2016.108 - PubMed
  14. Greenwood TA, Lazzeroni LC, Maihofer AX et al (2019) Genome-wide association of endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia (COGS) study. JAMA Psychiat 76:1274–1284. https://doi.org/10.1001/jamapsychiatry.2019.2850 - PubMed
  15. Hegde ML, Banerjee S, Hegde PM et al (2012) Enhancement of NEIL1 protein-initiated oxidized DNA base excision repair by heterogeneous nuclear ribonucleoprotein U (hnRNP-U) via direct interaction. J Biol Chem 287:34202–34211. https://doi.org/10.1074/jbc.M112.384032 - PubMed
  16. Hermey G (2009) The Vps10p-domain receptor family. Cell Mol Life Sci 66:2677–2689. https://doi.org/10.1007/s00018-009-0043-1 - PubMed
  17. Karlsson Linnér R, Biroli P, Kong E et al (2019) Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. Nat Genet 51:245–257. https://doi.org/10.1038/s41588-018-0309-3 - PubMed
  18. Lotharius J, Barg S, Wiekop P et al (2002) Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 277:38884–38894. https://doi.org/10.1074/jbc.M205518200 - PubMed
  19. Ma Q, Yang J, Milner TA et al (2017) SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease. JCI Insight. https://doi.org/10.1172/jci.insight.88995 - PubMed
  20. Madabhushi R, Pan L, Tsai L-H (2014) DNA damage and its links to neurodegeneration. Neuron 83:266–282. https://doi.org/10.1016/j.neuron.2014.06.034 - PubMed
  21. Madabhushi R, Gao F, Pfenning AR et al (2015) Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161:1592–1605. https://doi.org/10.1016/j.cell.2015.05.032 - PubMed
  22. Malik AR, Szydlowska K, Nizinska K et al (2019) SorCS2 controls functional expression of amino acid transporter EAAT3 and protects neurons from oxidative stress and epilepsy-induced pathology. Cell Rep 26:2792-2804.e6. https://doi.org/10.1016/j.celrep.2019.02.027 - PubMed
  23. Miki Y, Mori F, Seino Y et al (2018) Colocalization of Bunina bodies and TDP-43 inclusions in a case of sporadic amyotrophic lateral sclerosis with Lewy body-like hyaline inclusions. Neuropathology 38:521–528. https://doi.org/10.1111/neup.12484 - PubMed
  24. Mitra J, Guerrero EN, Hegde PM et al (2019) Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proc Natl Acad Sci USA 116:4696–4705. https://doi.org/10.1073/pnas.1818415116 - PubMed
  25. Montecucco A, Zanetta F, Biamonti G (2015) Molecular mechanisms of etoposide. EXCLI J 14:95–108. https://doi.org/10.17179/excli2015-561 - PubMed
  26. Morotomi-Yano K, Saito S, Adachi N, Yano K-I (2018) Dynamic behavior of DNA topoisomerase IIβ in response to DNA double-strand breaks. Sci Rep 8:10344. https://doi.org/10.1038/s41598-018-28690-6 - PubMed
  27. Mullaart E, Boerrigter ME, Ravid R et al (1990) Increased levels of DNA breaks in cerebral cortex of Alzheimer’s disease patients. Neurobiol Aging 11:169–173. https://doi.org/10.1016/0197-4580(90)90542-8 - PubMed
  28. Olsen D, Kaas M, Lundhede J et al (2019) Reduced alcohol seeking and withdrawal symptoms in mice lacking the BDNF receptor sorcs2. Front Pharmacol 10:499. https://doi.org/10.3389/fphar.2019.00499 - PubMed
  29. Olsen D, Wellner N, Kaas M et al (2021) Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice. Transl Psychiatry 11:74. https://doi.org/10.1038/s41398-021-01199-9 - PubMed
  30. Ortega-Martínez S (2015) Dexamethasone acts as a radiosensitizer in three astrocytoma cell lines via oxidative stress. Redox Biol 5:388–397. https://doi.org/10.1016/j.redox.2015.06.006 - PubMed
  31. Rampersad SN (2012) Multiple applications of Alamar Blue as an indicator of metabolic function and cellular health in cell viability bioassays. Sensors (basel) 12:12347–12360. https://doi.org/10.3390/s120912347 - PubMed
  32. Scholz D, Pöltl D, Genewsky A et al (2011) Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. J Neurochem 119:957–971. https://doi.org/10.1111/j.1471-4159.2011.07255.x - PubMed
  33. Shanbhag NM, Evans MD, Mao W et al (2019) Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease. Acta Neuropathol Commun 7:77. https://doi.org/10.1186/s40478-019-0723-5 - PubMed
  34. Smith AH, Ovesen PL, Skeldal S et al (2018) Risk locus identification ties alcohol withdrawal symptoms to SORCS2. Alcohol Clin Exp Res 42:2337–2348. https://doi.org/10.1111/acer.13890 - PubMed
  35. Suberbielle E, Sanchez PE, Kravitz AV et al (2013) Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat Neurosci 16:613–621. https://doi.org/10.1038/nn.3356 - PubMed
  36. Thadathil N, Hori R, Xiao J, Khan MM (2019) DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases. Chromosome Res 27:345–364. https://doi.org/10.1007/s10577-019-09617-x - PubMed
  37. Tuxworth RI, Taylor MJ, Martin Anduaga A et al (2019) Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration. Brain Commun 1:fcz005. https://doi.org/10.1093/braincomms/fcz005 - PubMed
  38. Wang H, Yang J, Schneider JA et al (2020) Genome-wide interaction analysis of pathological hallmarks in Alzheimer’s disease. Neurobiol Aging 93:61–68. https://doi.org/10.1016/j.neurobiolaging.2020.04.025 - PubMed
  39. Yang J, Ma Q, Dincheva I et al (2020) SorCS2 is required for social memory and trafficking of the NMDA receptor. Mol Psychiatry. https://doi.org/10.1038/s41380-020-0650-7 - PubMed

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