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Lithium facilitates removal of misfolded proteins and attenuated faulty interaction between mutant SOD1 and p-CREB (Ser133) through enhanced autophagy in mutant hSOD1G93A transfected neuronal cell lines

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Abstract

Abnormally protein aggregation and deposition are key pathological features of ALS, which may related with dysfunctional cellular autophagy. In the current study, we found that, compared with wtSOD1 cells, serum starvation treatment resulted in significant higher percentage of apoptosis in mutSOD1 cells; Lithium treatment exerted protection for those mutSOD1 cells, with decreased GFP-tagged mutant SOD1 protein aggregates deposition; Whereas, pre-treatment with Baf or 3-MA (autophagy inhibitors) blocked protection of lithium for mutant SOD1 cells, and induced increased GFP-tagged mutant SOD1 protein aggregation. Further, Western blots results showed that lithium treatment led to decrease of mutant hSOD1 protein levels in both Triton X-100 soluble and Triton X-100 insoluble fraction of mutSOD1 cells. Besides, improper binding of mutant SOD1 proteins’ aggregates with p-CREB (Ser133) (transcription factor) in mutSOD1 cells were demonstrated; whereas lithium treatment attenuated this fault interaction. In conclusion, our results showed that, in mutSOD1 cells, mutSOD1 protein aggregates were related with abnormal autophagic regulation. Lithium treatment could induce autophagy and enhance clearance of protein aggregates, further exerting protection on mutSOD1 cells. More importantly, we uncovered another distinct pathological role of mutSOD1 protein aggregates, that is abnormal binding with p-CREB (Ser133), an important transcription factor, which may play crucial role in the PI3K-Akt-CREB-AEG-1 signaling pathway.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

Baf:

Bafilomycin

co-IP:

co-Immunoprecipitation

CREB:

cAMP responsive element-binding protein

EBSS:

Earle’s balanced salt solution

GFP:

Green fluorescent protein

3-MA:

3-Methyladenine

MN:

Motor neuron

NSC34 cells:

Neuroblastoma × spinal cord cells

SOD1:

Superoxide dismutase 1

VDAC1:

Voltagedependent anion channel-1

References

  1. Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, Degroot S et al (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 126(3):385–399. https://doi.org/10.1007/s00401-013-1149-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A (2012) Neutrophil function: from mechanisms to disease. Annu Rev Immunol 30:459–489. https://doi.org/10.1146/annurev-immunol-020711-074942

    Article  CAS  PubMed  Google Scholar 

  3. An T, Shi P, Duan W, Zhang S, Yuan P, Li Z et al (2014) Oxidative stress and autophagic alteration in brainstem of SOD1-G93A mouse model of ALS. Mol Neurobiol 49(3):1435–1448. https://doi.org/10.1007/s12035-013-8623-3

    Article  CAS  PubMed  Google Scholar 

  4. Basso M, Samengo G, Nardo G, Massignan T, D’Alessandro G, Tartari S et al (2009) Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS ONE 4(12):e8130. https://doi.org/10.1371/journal.pone.0008130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292(5521):1552–1555. https://doi.org/10.1126/science.292.5521.1552

    Article  CAS  PubMed  Google Scholar 

  6. Bilsland LG, Sahai E, Kelly G, Golding M, Greensmith L, Schiavo G (2010) Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci USA 107(47):20523–20528. https://doi.org/10.1073/pnas.1006869107

    Article  PubMed  Google Scholar 

  7. Borchelt DR, Wong PC, Becher MW, Pardo CA, Lee MK, Xu ZS et al (1998) Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice. Neurobiol Dis 5(1):27–35. https://doi.org/10.1006/nbdi.1998.0178

    Article  CAS  PubMed  Google Scholar 

  8. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18(2):327–338

    Article  CAS  Google Scholar 

  9. Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E et al (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281(5384):1851–1854

    Article  CAS  Google Scholar 

  10. Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G et al (2013) Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9(9):1308–1320. https://doi.org/10.4161/auto.25188

    Article  CAS  PubMed  Google Scholar 

  11. Chen Y, Liu H, Guan Y, Wang Q, Zhou F, Jie L et al (2015) The altered autophagy mediated by TFEB in animal and cell models of amyotrophic lateral sclerosis. Am J Transl Res 7(9):1574–1587

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cheong H, Lu C, Lindsten T, Thompson CB (2012) Therapeutic targets in cancer cell metabolism and autophagy. Nat Biotechnol 30(7):671–678

    Article  CAS  Google Scholar 

  13. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366. https://doi.org/10.1146/annurev.biochem.75.101304.123901

    Article  CAS  PubMed  Google Scholar 

  14. Chiu CT, Chuang DM (2011) Neuroprotective action of lithium in disorders of the central nervous system. J Cent South Univ Med Sci 36(6):461–476

    CAS  Google Scholar 

  15. Cozzolino M, Pesaresi MG, Amori I, Crosio C, Ferri A, Nencini M et al (2009) Oligomerization of mutant SOD1 in mitochondria of motoneuronal cells drives mitochondrial damage and cell toxicity. Antioxid Redox Signal 11(7):1547–1558. https://doi.org/10.1089/ARS.2009.2545

    Article  CAS  PubMed  Google Scholar 

  16. Damme M, Suntio T, Saftig P, Eskelinen EL (2015) Autophagy in neuronal cells: general principles and physiological and pathological functions. Acta Neuropathol 129(3):337–362. https://doi.org/10.1007/s00401-014-1361-4

    Article  CAS  PubMed  Google Scholar 

  17. Dobson CM (2003) Protein folding and misfolding. Nature 426(6968):884–890. https://doi.org/10.1038/nature02261

    Article  CAS  PubMed  Google Scholar 

  18. D’Souza R, Rajji TK, Mulsant BH, Pollock BG (2011) Use of lithium in the treatment of bipolar disorder in late-life. Curr Psychiatry Rep 13(6):488–492

    Article  Google Scholar 

  19. Durham HD, Roy J, Dong L, Figlewicz DA (1997) Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS. J Neuropathol Exp Neurol 56(5):523–530

    Article  CAS  Google Scholar 

  20. Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM (2008) Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155(3):567–572

    Article  CAS  Google Scholar 

  21. Ferri A, Fiorenzo P, Nencini M, Cozzolino M, Pesaresi MG, Valle C et al (2010) Glutaredoxin 2 prevents aggregation of mutant SOD1 in mitochondria and abolishes its toxicity. Hum Mol Genet 19(22):4529–4542. https://doi.org/10.1093/hmg/ddq383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Forlenza OV, De-Paula VJ, Diniz BS (2014) Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem Neurosci 5(6):443–450. https://doi.org/10.1021/cn5000309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fornai F, Longone P, Ferrucci M, Lenzi P, Isidoro C, Ruggieri S et al (2008) Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy 4(4):527–530

    Article  CAS  Google Scholar 

  24. Gal J, Kuang L, Barnett KR, Zhu BZ, Shissler SC, Korotkov KV et al (2016) ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics. Acta Neuropathol 132(4):563–576. https://doi.org/10.1007/s00401-016-1601-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gal J, Strom AL, Kwinter DM, Kilty R, Zhang J, Shi P et al (2009) Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem 111(4):1062–1073. https://doi.org/10.1111/j.1471-4159.2009.06388.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889. https://doi.org/10.1038/nature04724

    Article  CAS  PubMed  Google Scholar 

  27. Jaarsma D, Teuling E, Haasdijk ED, De Zeeuw CI, Hoogenraad CC (2008) Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci 28(9):2075–2088. https://doi.org/10.1523/JNEUROSCI.5258-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Koh SH, Roh H, Lee SM, Kim HJ, Kim M, Lee KW et al (2005) Phosphatidylinositol 3-kinase activator reduces motor neuronal cell death induced by G93A or A4 V mutant SOD1 gene. Toxicology 213(1–2):45–55. https://doi.org/10.1016/j.tox.2005.05.009

    Article  CAS  PubMed  Google Scholar 

  29. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884. https://doi.org/10.1038/nature04723

    Article  CAS  PubMed  Google Scholar 

  30. Li L, Zhang X, Le W (2008) Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy 4(3):290–293

    Article  CAS  Google Scholar 

  31. Li Y, Guo Y, Wang X, Yu X, Duan W, Hong K et al (2015) 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 298:12–25. https://doi.org/10.1016/j.neuroscience.2015.03.061

    Article  CAS  PubMed  Google Scholar 

  32. Maday S (2016) Mechanisms of neuronal homeostasis: autophagy in the axon. Brain Res 1649(Pt B):143–150. https://doi.org/10.1016/j.brainres.2016.03.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Magri A, Belfiore R, Reina S, Tomasello MF, Di Rosa MC, Guarino F et al (2016) Hexokinase I N-terminal based peptide prevents the VDAC1-SOD1 G93A interaction and re-establishes ALS cell viability. Sci Rep 6:34802. https://doi.org/10.1038/srep34802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nassif M, Valenzuela V, Rojas-Rivera D, Vidal R, Matus S, Castillo K et al (2014) Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy 10(7):1256–1271. https://doi.org/10.4161/auto.28784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Park JH, Jang HR, Lee IY, Oh HK, Choi EJ, Rhim H et al (2017) Amyotrophic lateral sclerosis-related mutant superoxide dismutase 1 aggregates inhibit 14-3-3-mediated cell survival by sequestration into the JUNQ compartment. Hum Mol Genet 26(18):3615–3629. https://doi.org/10.1093/hmg/ddx250

    Article  CAS  PubMed  Google Scholar 

  36. Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D et al (2004) Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43(1):19–30. https://doi.org/10.1016/j.neuron.2004.06.021

    Article  CAS  PubMed  Google Scholar 

  37. Pasquali L, Longone P, Isidoro C, Ruggieri S, Paparelli A, Fornai F (2009) Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve 40(2):173–194

    Article  CAS  Google Scholar 

  38. Pedrini S, Sau D, Guareschi S, Bogush M, Brown RH Jr, Naniche N et al (2010) ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2. Hum Mol Genet 19(15):2974–2986. https://doi.org/10.1093/hmg/ddq202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Perera ND, Sheean RK, Lau CL, Shin YS, Beart PM, Horne MK et al (2018) Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression. Autophagy 14(3):534–551. https://doi.org/10.1080/15548627.2017.1385674

    Article  CAS  PubMed  Google Scholar 

  40. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10(Suppl):S10–S17. https://doi.org/10.1038/nm1066

    Article  CAS  PubMed  Google Scholar 

  41. Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6(11):891–898. https://doi.org/10.1038/nrm1742

    Article  CAS  PubMed  Google Scholar 

  42. Ryves WJ, Harwood AJ (2001) Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 280(3):720–725

    Article  CAS  Google Scholar 

  43. Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M et al (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170(7):1101–1111. https://doi.org/10.1083/jcb.200504035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sarkar S, Rubinsztein DC (2006) Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. Autophagy 2(2):132–134

    Article  CAS  Google Scholar 

  45. Sasaki S (2011) Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 70(5):349–359. https://doi.org/10.1097/NEN.0b013e3182160690

    Article  PubMed  Google Scholar 

  46. Sheng Y, Chattopadhyay M, Whitelegge J, Valentine JS (2012) SOD1 aggregation and ALS: role of metallation states and disulfide status. Curr Top Med Chem 12(22):2560–2572

    Article  CAS  Google Scholar 

  47. Shi P, Gal J, Kwinter DM, Liu X, Zhu H (2010) Mitochondrial dysfunction in amyotrophic lateral sclerosis. Biochim Biophys Acta 1802(1):45–51. https://doi.org/10.1016/j.bbadis.2009.08.012

    Article  CAS  PubMed  Google Scholar 

  48. Strong MJ, Kesavapany S, Pant HC (2005) The pathobiology of amyotrophic lateral sclerosis: a proteinopathy? J Neuropathol Exp Neurol 64(8):649–664

    Article  CAS  Google Scholar 

  49. Tian F, Morimoto N, Liu W, Ohta Y, Deguchi K, Miyazaki K et al (2011) In vivo optical imaging of motor neuron autophagy in a mouse model of amyotrophic lateral sclerosis. Autophagy 7(9):985–992

    Article  CAS  Google Scholar 

  50. Tokuda E, Brannstrom T, Andersen PM, Marklund SL (2016) Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase. Acta Neuropathol Commun 4:6. https://doi.org/10.1186/s40478-016-0274-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Valenzuela V, Nassif M, Hetz C (2018) Unraveling the role of motoneuron autophagy in ALS. Autophagy 14(4):733–737. https://doi.org/10.1080/15548627.2018.1432327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wada A, Yokoo H, Yanagita T, Kobayashi H (2005) Lithium: potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. J Pharmacol Sci 99(4):307–321

    Article  CAS  Google Scholar 

  53. Wang IF, Guo BS, Liu YC, Wu CC, Yang CH, Tsai KJ et al (2012) Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci USA 109(37):15024–15029. https://doi.org/10.1073/pnas.1206362109

    Article  CAS  PubMed  Google Scholar 

  54. Webster CP, Smith EF, Bauer CS, Moller A, Hautbergue GM, Ferraiuolo L et al (2016) The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J 35(15):1656–1676. https://doi.org/10.15252/embj.201694401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Williamson TL, Cleveland DW (1999) Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 2(1):50–56. https://doi.org/10.1038/4553

    Article  CAS  PubMed  Google Scholar 

  56. Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR et al (2010) Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 285(14):10850–10861

    Article  CAS  Google Scholar 

  57. Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y (1998) Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 23(1):33–42

    Article  CAS  Google Scholar 

  58. Yin X, Ren M, Jiang H, Cui S, Wang S, Jiang H et al (2015) Downregulated AEG-1 together with inhibited PI3K/Akt pathway is associated with reduced viability of motor neurons in an ALS model. Mol Cell Neurosci 68:303–313. https://doi.org/10.1016/j.mcn.2015.08.009

    Article  CAS  PubMed  Google Scholar 

  59. Yuan S, Zhang ZW, Li ZL (2017) Cell death-autophagy loop and glutamate-glutamine cycle in amyotrophic lateral sclerosis. Front Mol Neurosci 10:231. https://doi.org/10.3389/fnmol.2017.00231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang X, Chen S, Song L, Tang Y, Shen Y, Jia L et al (2014) MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis. Autophagy 10(4):588–602. https://doi.org/10.4161/auto.27710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang X, Li L, Chen S, Yang D, Wang Y, Zhang X et al (2011) Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7(4):412–425

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Dr. Neil (Cashman of University of British Columbia, Canada) for providing the NSC34 cells. In addition, we wish to thank Shangjin Cui of National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute (CAAS) for assistance with our work, and Karan of the Editage for excellent editorial assistance.

Funding

This research was funded by Natural Science Foundation of China (Grant Number 81571227).

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Authors and Affiliations

  1. Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China

    Xiang Yin

  2. Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China

    Xiang Yin, Shuyu Wang, Xudong Wang, Yueqing Yang, Hongquan Jiang, Tianhang Wang, Ying Wang, Chunting Zhang & Honglin Feng

  3. Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, People’s Republic of China

    Honglin Feng

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Contributions

FHL directed the whole study. FHL, YX and WSY designed the experiments. YX, WSY, WXD, YYQ, WTH and ZCT performed the experiments. JHQ and WY analyzed the data. JHQ and FHL contributed supplying reagents and materials and supported analysis. YX, WSY, WXD, YYQ, JHQ and WTH participated in the discussion. YX and FHL wrote the manuscript.

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Correspondence to Honglin Feng.

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Yin, X., Wang, S., Wang, X. et al. Lithium facilitates removal of misfolded proteins and attenuated faulty interaction between mutant SOD1 and p-CREB (Ser133) through enhanced autophagy in mutant hSOD1G93A transfected neuronal cell lines. Mol Biol Rep 46, 6299–6309 (2019). https://doi.org/10.1007/s11033-019-05071-4

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