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Impaired Pentose Phosphate Pathway in the Spinal Cord of the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

  • Tesfaye Wolde Tefera
  • Katherine Bartlett
  • Shirley S. Tran
  • Mark P. Hodson
  • Karin BorgesEmail author
Article

Abstract

Impairments in energy metabolism in amyotrophic lateral sclerosis (ALS) have long been known. However, the changes in the energy-producing pathways in ALS are not comprehensively understood. To investigate specific alterations in glucose metabolism in glycolytic, pentose phosphate, and TCA cycle pathways, we injected uniformly labeled [U-13C]glucose to wild-type and hSOD1G93A mice at symptom onset (80 days). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), levels of metabolites were determined in extracts of the cortex and spinal cord. In addition, the activities of several enzymes involved in glucose metabolism were quantified. In the spinal cord, the levels of pentose phosphate pathway (PPP) intermediate ribose 5-phosphate (p = 0.037) were reduced by 37% in hSOD1G93A mice, while the % 13C enrichments in glucose 6-phosphate were increased threefold. The maximal activities of the enzyme glucose 6-phosphate dehydrogenase were decreased by 24% in the spinal cord (p = 0.005), suggesting perturbations in the PPP. The total amount of pyruvate in the cortex (p = 0.039) was reduced by 20% in hSOD1G93A mice. Also, the activities of the glycolytic enzyme pyruvate kinase were reduced in the cortex by 31% (p = 0.002), indicating alterations in glycolysis. No significant differences were seen in the total amounts as well as % 13C enrichments in most TCA cycle intermediates, suggesting largely normal TCA cycle function. On the other hand, oxoglutarate dehydrogenase activity was decreased in the cortex, which may indicate increased oxidative stress. Overall, this study revealed decreased activity of the PPP in the spinal cord and alterations in glycolysis in hSOD1G93A mouse CNS tissues at the early symptomatic stage of disease.

Keywords

Energy metabolism Glycolysis Liquid chromatography-tandem mass spectrometry Motor neuron disease Pentose phosphate pathway TCA cycle 

Notes

Acknowledgements

We wish to thank the Queensland Brain Institute and Dr. Shuyan Ngo for providing animals. TWT is a recipient of The University of Queensland International scholarship.

Funding

This work was supported by the Motor Neurone Disease Research Institute Australia to KB (grant number: GIA 1704).

Compliance with Ethical Standards

All animal experiments were approved by the University of Queensland Animal Ethics Committee (SBMS 128/14) and followed the guidelines of the Queensland Animal Care and Protection Act 2001.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12035_2019_1485_MOESM1_ESM.docx (20 kb)
Supplementary Table 1 (DOCX 19 kb)

References

  1. 1.
    Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377(9769):942–955.  https://doi.org/10.1016/S0140-6736(10)61156-7 CrossRefPubMedGoogle Scholar
  2. 2.
    Chen S, Sayana P, Zhang X, Le W (2013) Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener 8:28.  https://doi.org/10.1186/1750-1326-8-28 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319(5870):1668–1672.  https://doi.org/10.1126/science.1154584 CrossRefPubMedGoogle Scholar
  4. 4.
    Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326(22):1464–1468.  https://doi.org/10.1056/NEJM199205283262204 CrossRefPubMedGoogle Scholar
  5. 5.
    Rothstein JD (1995) Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. Adv Neurol 68:7–20 discussion 21-27PubMedGoogle Scholar
  6. 6.
    Shaw PJ, Ince PG, Falkous G, Mantle D (1995) Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol 38(4):691–695.  https://doi.org/10.1002/ana.410380424 CrossRefPubMedGoogle Scholar
  7. 7.
    Dupuis L, Oudart H, Rene F, Gonzalez de Aguilar JL, Loeffler JP (2004) Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A 101(30):11159–11164.  https://doi.org/10.1073/pnas.0402026101 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Dupuis L, Pradat PF, Ludolph AC, Loeffler JP (2011) Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol 10(1):75–82.  https://doi.org/10.1016/S1474-4422(10)70224-6 CrossRefPubMedGoogle Scholar
  9. 9.
    Korner S, Hendricks M, Kollewe K, Zapf A, Dengler R, Silani V, Petri S (2013) Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis (ALS): impact on quality of life and therapeutic options. BMC Neurol 13:84.  https://doi.org/10.1186/1471-2377-13-84 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Desport JC, Preux PM, Magy L, Boirie Y, Vallat JM, Beaufrere B, Couratier P (2001) Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis. Am J Clin Nutr 74(3):328–334CrossRefGoogle Scholar
  11. 11.
    Browne SE, Yang L, DiMauro JP, Fuller SW, Licata SC, Beal MF (2006) Bioenergetic abnormalities in discrete cerebral motor pathways presage spinal cord pathology in the G93A SOD1 mouse model of ALS. Neurobiol Dis 22(3):599–610.  https://doi.org/10.1016/j.nbd.2006.01.001 CrossRefPubMedGoogle Scholar
  12. 12.
    Miyazaki K, Masamoto K, Morimoto N, Kurata T, Mimoto T, Obata T, Kanno I, Abe K (2012) Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration of ALS model mice. J Cereb Blood Flow Metab 32(3):456–467.  https://doi.org/10.1038/jcbfm.2011.155 CrossRefPubMedGoogle Scholar
  13. 13.
    Dalakas MC, Hatazawa J, Brooks RA, Di Chiro G (1987) Lowered cerebral glucose utilization in amyotrophic lateral sclerosis. Ann Neurol 22(5):580–586.  https://doi.org/10.1002/ana.410220504 CrossRefPubMedGoogle Scholar
  14. 14.
    Tefera TW, Borges K (2018) Neuronal glucose metabolism is impaired while astrocytic TCA cycling is unaffected at symptomatic stages in the hSOD1(G93A) mouse model of amyotrophic lateral sclerosis. J Cereb Blood Flow Metab:271678X18764775.  https://doi.org/10.1177/0271678X18764775
  15. 15.
    Barber SC, Mead RJ, Shaw PJ (2006) Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta 1762(11–12):1051–1067.  https://doi.org/10.1016/j.bbadis.2006.03.008 CrossRefPubMedGoogle Scholar
  16. 16.
    Niedzielska E, Smaga I, Gawlik M, Moniczewski A, Stankowicz P, Pera J, Filip M (2016) Oxidative stress in neurodegenerative diseases. Mol Neurobiol 53(6):4094–4125.  https://doi.org/10.1007/s12035-015-9337-5 CrossRefPubMedGoogle Scholar
  17. 17.
    Veyrat-Durebex C, Corcia P, Piver E, Devos D, Dangoumau A, Gouel F, Vourc'h P, Emond P et al (2015) Disruption of TCA cycle and glutamate metabolism identified by metabolomics in an in vitro model of amyotrophic lateral sclerosis. Mol Neurobiol 53:6910–6924.  https://doi.org/10.1007/s12035-015-9567-6 CrossRefPubMedGoogle Scholar
  18. 18.
    D'Arrigo A, Colavito D, Pena-Altamira E, Fabris M, Dam M, Contestabile A, Leon A (2010) Transcriptional profiling in the lumbar spinal cord of a mouse model of amyotrophic lateral sclerosis: a role for wild-type superoxide dismutase 1 in sporadic disease? J Mol Neurosci 41(3):404–415.  https://doi.org/10.1007/s12031-010-9332-2 CrossRefPubMedGoogle Scholar
  19. 19.
    Ferraiuolo L, Higginbottom A, Heath PR, Barber S, Greenald D, Kirby J, Shaw PJ (2011) Dysregulation of astrocyte-motoneuron cross-talk in mutant superoxide dismutase 1-related amyotrophic lateral sclerosis. Brain 134(Pt 9):2627–2641.  https://doi.org/10.1093/brain/awr193 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tefera TW, Borges K (2016) Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments. Front Neurosci 10:611.  https://doi.org/10.3389/fnins.2016.00611 CrossRefPubMedGoogle Scholar
  21. 21.
    Tefera TW, Tan KN, McDonald TS, Borges K (2016) Alternative fuels in epilepsy and amyotrophic lateral sclerosis. Neurochem Res 42:1610–1620.  https://doi.org/10.1007/s11064-016-2106-7 CrossRefPubMedGoogle Scholar
  22. 22.
    Le Belle JE, Harris NG, Williams SR, Bhakoo KK (2002) A comparison of cell and tissue extraction techniques using high-resolution 1H-NMR spectroscopy. NMR Biomed 15(1):37–44CrossRefGoogle Scholar
  23. 23.
    McDonald TS, Carrasco-Pozo C, Hodson MP, Borges K (2017) Alterations in cytosolic and mitochondrial [U-13C]glucose metabolism in a chronic epilepsy mouse model. eNeuro 4(1):ENEURO.0341–ENEU16.2017.  https://doi.org/10.1523/ENEURO.0341-16.2017 CrossRefGoogle Scholar
  24. 24.
    Medina-Torres CE, van Eps AW, Nielsen LK, Hodson MP (2015) A liquid chromatography-tandem mass spectrometry-based investigation of the lamellar interstitial metabolome in healthy horses and during experimental laminitis induction. Vet J 206(2):161–169.  https://doi.org/10.1016/j.tvjl.2015.07.031 CrossRefPubMedGoogle Scholar
  25. 25.
    Tan KN, Simmons D, Carrasco-Pozo C, Borges K (2018) Triheptanoin protects against status epilepticus-induced hippocampal mitochondrial dysfunctions, oxidative stress and neuronal degeneration. J Neurochem 144(4):431–442.  https://doi.org/10.1111/jnc.14275 CrossRefPubMedGoogle Scholar
  26. 26.
    Kirby J, Halligan E, Baptista MJ, Allen S, Heath PR, Holden H, Barber SC, Loynes CA et al (2005) Mutant SOD1 alters the motor neuronal transcriptome: implications for familial ALS. Brain 128(Pt 7):1686–1706.  https://doi.org/10.1093/brain/awh503 CrossRefPubMedGoogle Scholar
  27. 27.
    Bowling AC, Schulz JB, Brown RH Jr, Beal MF (1993) Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 61(6):2322–2325CrossRefGoogle Scholar
  28. 28.
    Mitsumoto H, Santella RM, Liu X, Bogdanov M, Zipprich J, Wu HC, Mahata J, Kilty M et al (2008) Oxidative stress biomarkers in sporadic ALS. Amyotroph Lateral Scler 9(3):177–183.  https://doi.org/10.1080/17482960801933942 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH (2004) Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 62(10):1758–1765CrossRefGoogle Scholar
  30. 30.
    Allen S, Heath PR, Kirby J, Wharton SB, Cookson MR, Menzies FM, Banks RE, Shaw PJ (2003) Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant defenses, and nitric oxide synthetic pathways. J Biol Chem 278(8):6371–6383.  https://doi.org/10.1074/jbc.M209915200 CrossRefPubMedGoogle Scholar
  31. 31.
    Chen T, Turner BJ, Beart PM, Sheehan-Hennessy L, Elekwachi C, Muyderman H (2017) Glutathione monoethyl ester prevents TDP-43 pathology in motor neuronal NSC-34 cells. Neurochem Int 112:278–287.  https://doi.org/10.1016/j.neuint.2017.08.009 CrossRefPubMedGoogle Scholar
  32. 32.
    Chi L, Ke Y, Luo C, Gozal D, Liu R (2007) Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo. Neuroscience 144(3):991–1003.  https://doi.org/10.1016/j.neuroscience.2006.09.064 CrossRefPubMedGoogle Scholar
  33. 33.
    Vargas MR, Johnson DA, Johnson JA (2011) Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1(G93A) mice model. Neurobiol Dis 43(3):543–551.  https://doi.org/10.1016/j.nbd.2011.04.025 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Santa-Cruz LD, Tapia R (2014) Role of energy metabolic deficits and oxidative stress in excitotoxic spinal motor neuron degeneration in vivo. ASN Neuro 6(2):AN20130046.  https://doi.org/10.1042/AN20130046 CrossRefGoogle Scholar
  35. 35.
    Wang XS, Simmons Z, Liu W, Boyer PJ, Connor JR (2006) Differential expression of genes in amyotrophic lateral sclerosis revealed by profiling the post mortem cortex. Amyotroph Lateral Scler 7(4):201–210.  https://doi.org/10.1080/17482960600947689 CrossRefPubMedGoogle Scholar
  36. 36.
    Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 11(6):747–752.  https://doi.org/10.1038/ncb1881 CrossRefPubMedGoogle Scholar
  37. 37.
    Dienel GA (2014) Chapter 3 - energy metabolism in the brain. In: From molecules to networks, 3rd edn. Academic, Boston, pp. 53–117.  https://doi.org/10.1016/B978-0-12-397179-1.00003-8 CrossRefGoogle Scholar
  38. 38.
    D'Alessandro G, Calcagno E, Tartari S, Rizzardini M, Invernizzi RW, Cantoni L (2011) Glutamate and glutathione interplay in a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism. Neurobiol Dis 43(2):346–355.  https://doi.org/10.1016/j.nbd.2011.04.003 CrossRefPubMedGoogle Scholar
  39. 39.
    Siciliano G, Pastorini E, Pasquali L, Manca ML, Iudice A, Murri L (2001) Impaired oxidative metabolism in exercising muscle from ALS patients. J Neurol Sci 191(1–2):61–65CrossRefGoogle Scholar
  40. 40.
    Siciliano G, D'Avino C, Del Corona A, Barsacchi R, Kusmic C, Rocchi A, Pastorini E, Murri L (2002) Impaired oxidative metabolism and lipid peroxidation in exercising muscle from ALS patients. Amyotroph Lateral Scler Other Motor Neuron Disord 3(2):57–62.  https://doi.org/10.1080/146608202760196011 CrossRefPubMedGoogle Scholar
  41. 41.
    Dodge JC, Treleaven CM, Fidler JA, Tamsett TJ, Bao C, Searles M, Taksir TV, Misra K et al (2013) Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. Proc Natl Acad Sci U S A 110(26):10812–10817.  https://doi.org/10.1073/pnas.1308421110 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Tretter L, Adam-Vizi V (2000) Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 20(24):8972–8979CrossRefGoogle Scholar
  43. 43.
    Mailloux RJ, Beriault R, Lemire J, Singh R, Chenier DR, Hamel RD, Appanna VD (2007) The tricarboxylic acid cycle, an ancient metabolic network with a novel twist. PLoS One 2(8):e690.  https://doi.org/10.1371/journal.pone.0000690 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Tefera TW, Wong Y, Barkl-Luke ME, Ngo ST, Thomas NK, McDonald TS, Borges K (2016) Triheptanoin protects motor neurons and delays the onset of motor symptoms in a mouse model of amyotrophic lateral sclerosis. PLoS One 11(8):e0161816.  https://doi.org/10.1371/journal.pone.0161816 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ari C, Poff AM, Held HE, Landon CS, Goldhagen CR, Mavromates N, D'Agostino DP (2014) Metabolic therapy with Deanna protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model. PLoS One 9(7):e103526.  https://doi.org/10.1371/journal.pone.0103526 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Matthews RT, Yang L, Browne S, Baik M, Beal MF (1998) Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A 95 (15):8892–8897Google Scholar
  47. 47.
    Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP, Beckman JS, Barbeito L, Radi R (2008) Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 28(16):4115–4122.  https://doi.org/10.1523/JNEUROSCI.5308-07.2008
  48. 48.
    Miquel E, Cassina A, Martinez-Palma L, Souza JM, Bolatto C, Rodriguez-Bottero S, Logan A, Smith RA, Murphy MP, Barbeito L, Radi R, Cassina P (2014) Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis. Free Radic Biol Med 70:204–213.  https://doi.org/10.1016/j.freeradbiomed.2014.02.019
  49. 49.
    Zhao W, Varghese M, Vempati P, Dzhun A, Cheng A, Wang J, Lange D, Bilski A et al (2012) Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease. PLoS One 7(11):e49191.  https://doi.org/10.1371/journal.pone.0049191 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, Suh J, Humala N, Thiyagarajan M et al (2006) A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci 7(29):29.  https://doi.org/10.1186/1471-2202-7-29 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Scott A (2017) Drug therapy: on the treatment trail for ALS. Nature 550(7676):S120–S121.  https://doi.org/10.1038/550S120a CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Neurological Disorders and Metabolism Lab, School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia
  2. 2.Australian Institute for Bioengineering and NanotechnologyThe University of QueenslandBrisbaneAustralia
  3. 3.Metabolomics Australia Queensland Node, Australian Institute for Bioengineering and NanotechnologyThe University of QueenslandBrisbaneAustralia
  4. 4.School of PharmacyThe University of QueenslandBrisbaneAustralia
  5. 5.Metabolomics Research LaboratoryVictor Chang Cardiac Research InstituteSydneyAustralia

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