Abstract

Research Article

Carbonic Anhydrase I modifies SOD1-induced motor neuron toxicity in Drosophila via ER stress pathway

Jian Liu*, Deyi Lu, Xiao Peng, Xuejiao Jia, Guiyi Li, Na Tan, Zhen Wei, Xinzhu Fei, Xiaochen Liu, Tatsuhiko Kadowaki and Jian Liu

Published: 01 August, 2019 | Volume 3 - Issue 2 | Pages: 135-144

Background: Drosophila models of amyotrophic lateral sclerosis (ALS) have been widely used in understanding molecular mechanisms of ALS pathogenesis as well as discovering potential targets for therapeutic drugs. Mutations in the copper/zinc superoxide dismutase (SOD1) cause ALS by gain of toxic functions and induce toxicity in fly motor neurons.

Results: In this study, we have determined that human carbonic anhydrase I (CA1) can alleviate mutant SOD1-induced motor neuron toxicity in the transgenic fly model of ALS. Interestingly, we found that motor neuron expression of CA1 could independently induce locomotion defect as well as decreasing the survival rate. In addition, CA1-induced toxicity in motor neurons is anhydrase activity-dependent. Mechanistically, we identified that both SOD1- and CA1-induced toxicity involve the activation of eIF2α in the ER stress response pathway. Downstream activation of the JNK pathway has also been implicated in the induced toxicity.

Conclusion: Our results have confirmed that SOD1-induced toxicity in fly motor neuron also involves endoplasmic reticulum (ER) stress pathway. More importantly, we have discovered a new cellular role that CA1 plays by antagonizing mutant SOD1-induced toxicity in motor neurons involving the ER stress pathway. Such information can be potentially useful for further understanding disease mechanisms and developing therapeutic targets for ALS. 

Read Full Article HTML DOI: 10.29328/journal.jnnd.1001024 Cite this Article Read Full Article PDF

Keywords:

Carbonic Anhydrase 1 (CA1); SOD1; ALS; Drosophila; Motor neuron; Endoplasmic Reticulum (ER) stress

References

  1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, et al. Amyotrophic lateral sclerosis. Lancet. 2011; 377: 942-955. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21296405
  2. Mathis S, Goizet C, Soulages A, Vallat JM, Masson GL. Genetics of amyotrophic lateral sclerosis: A review. J Neurol Sci. 2019; 399: 217-226. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30870681
  3. Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016; 539: 197-206. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27830784
  4. Liu X, Lu D, Bowser R, Liu J. Expression of Carbonic Anhydrase I in Motor Neurons and Alterations in ALS. Int J Mol Sci. 2016; 17. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27809276
  5. Tolvanen ME, Ortutay C, Barker HR, Aspatwar A, Patrikainen M, et al. Analysis of evolution of carbonic anhydrases IV and XV reveals a rich history of gene duplications and a new group of isozymes. Bioorg Med Chem. 2013; 21: 1503-1510. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23022279
  6. Frost SC. Physiological functions of the alpha class of carbonic anhydrases. Subcell Biochem. 2014; 75: 9-30. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24146372
  7. Syrjanen L, Tolvanen ME, Hilvo M, Vullo D, Carta F, et al. Characterization, bioinformatic analysis and dithiocarbamate inhibition studies of two new alpha-carbonic anhydrases, CAH1 and CAH2, from the fruit fly Drosophila melanogaster. Bioorg Med Chem. 2013; 21: 1516-1521. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22989910
  8. Overend G, Luo Y, Henderson L, Douglas AE, Davies SA, et al. Molecular mechanism and functional significance of acid generation in the Drosophila midgut. Sci Rep. 2016; 6: 27242. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27250760
  9. Chang X, Han J, Zhao Y, Yan X, Sun S, et al. Increased expression of carbonic anhydrase I in the synovium of patients with ankylosing spondylitis. BMC Musculoskelet Disord. 2010; 11: 279. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21143847
  10. Connor DE Jr, Chaitanya GV, Chittiboina P, McCarthy P, Scott LK, et al. Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage. Pathophysiology. 2017; 24: 169-183. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28549769
  11. Gao BB, Clermont A, Rook S, Fonda SJ, Srinivasan VJ, et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med. 2007; 13: 181-188. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17259996
  12. Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, et al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry. 2000; 5: 142-149. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10822341
  13. Mentese A, Erkut N, Demir S, Yaman SO, Sumer A, et al. Serum carbonic anhydrase I and II autoantibodies in patients with chronic lymphocytic leukaemia. Cent Eur J Immunol. 2018; 43: 276-280. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30588172
  14. Mentese A, Fidan E, Alver A, Demir S, Yaman SO, et al. Detection of autoantibodies against carbonic anhydrase I and II in the plasma of patients with gastric cancer. Cent Eur J Immunol. 2017; 42: 73-77. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28680333
  15. Ruiz Esparza-Garrido R, Velazquez-Flores MA, Diegoperez-Ramirez J, López-Aguilar E, Siordia-Reyes G, et al. A proteomic approach of pediatric astrocytomas: MiRNAs and network insight. J Proteomics. 2013; 94: 162-175. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24060999
  16. Torella D, Ellison GM, Torella M, Vicinanza C, Aquila I, et al. Carbonic anhydrase activation is associated with worsened pathological remodeling in human ischemic diabetic cardiomyopathy. J Am Heart Assoc. 2014; 3: e000434. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24670789
  17. Visanji NP, Wong JC, Wang SX, Cappel B, Kleinschmidt-Demasters BK, et al. A proteomic analysis of pediatric seizure cases associated with astrocytic inclusions. Epilepsia. 2012; 53: 50-54. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22220588
  18. Yamanishi H, Murakami H, Ikeda Y, Abe M, Kumagi T, et al. Regulatory dendritic cells pulsed with carbonic anhydrase I protect mice from colitis induced by CD4+CD25- T cells. J Immunol. 2012; 188: 2164-2172. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22291189
  19. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993; 362: 59-62. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8332197
  20. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet. 1996; 13: 43-47. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8673102
  21. Saccon RA, Bunton-Stasyshyn RK, Fisher EM, Fratta P. Is SOD1 loss of function involved in amyotrophic lateral Sclerosis? Brain. 2013; 136: 2342-2358. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23687121
  22. Fujisawa T, Homma K, Yamaguchi N, Kadowaki H, Tsuburaya N, et al. A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. Ann Neurol. 2012; 72: 739-749. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23280792
  23. Nishitoh H, Kadowaki H, Nagai A, Maruyama T, Yokota T, et al. ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev. 2008; 22: 1451-1464. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18519638
  24. Watson MR, Lagow RD, Xu K, Zhang B, Bonini NM. A drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1. J Biol Chem. 2008; 283: 24972-24981. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18596033
  25. Sahin A, Held A, Bredvik K, Major P, Achilli TM, et al. Human SOD1 ALS Mutations in a Drosophila Knock-In Model Cause Severe Phenotypes and Reveal Dosage-Sensitive Gain- and Loss-of-Function Components. Genetics. 2017; 205: 707-723. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27974499
  26. Mohanty AK, Trehan AK. Puerperal uterine inversion: analysis of three cases managed by repositioning, and literature review. J Obstet Gynaecol. 1998; 18: 353-354. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15512108
  27. Romero E, Cha GH, Verstreken P, Ly CV, Hughes RE, et al. Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. Neuron; 2008; 57: 27-40. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18184562
  28. Sanyal S. Genomic mapping and expression patterns of C380, OK6 and D42 enhancer trap lines in the larval nervous system of Drosophila. Gene Expr Patterns. 2009; 9: 371-380. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19602393
  29. Li J, Parker B, Martyn C, Natarajan C, Guo J. The PMP22 gene and its related diseases. Mol Neurobiol. 2013; 47: 673-698. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23224996
  30. Pun S, Santos AF, Saxena S, Xu L, Caroni P. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci. 2006; 9: 408-419. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16474388
  31. Ratnaparkhi A, Lawless GM, Schweizer FE, Golshani P, Jackson GR. A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS One. 2008; 3: e2334. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18523548
  32. Steyaert J, Scheveneels W, Vanneste J, Van Damme P, Robberecht W, et al. FUS-induced neurotoxicity in Drosophila is prevented by downregulating nucleocytoplasmic transport proteins. Hum Mol Genet. 2018; 27: 4103-4116. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30379317
  33. Kieran D, Hafezparast M, Bohnert S, Dick JR, Martin J, et al. A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice. J Cell Biol. 2005; 169: 561-567. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15911875
  34. Wang W, Wen D, Duan W, Yin J, Cui C, et al. Systemic administration of scAAV9-IGF1 extends survival in SOD1(G93A) ALS mice via inhibiting p38 MAPK and the JNK-mediated apoptosis pathway. Brain Res Bull. 2018; 139: 203-210. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29499331
  35. Pinal N, Calleja M, Morata G. Pro-apoptotic and pro-proliferation functions of the JNK pathway of Drosophila: roles in cell competition, tumorigenesis and regeneration. Open Biol. 2019; 9: 180256. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30836847
  36. Li Y, Ray P, Rao EJ, Shi C, Guo W, et al. A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci USA. 2010; 107: 3169-3174. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20133767
  37. Liang Z, Xue Y, Behravan G, Jonsson BH, Lindskog S. Importance of the conserved active-site residues Tyr7, Glu106 and Thr199 for the catalytic function of human carbonic anhydrase II. Eur J Biochem. 1993; 211: 821-827. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8436138
  38. Liu D, Zhang M, Yin H. Signaling pathways involved in endoplasmic reticulum stress-induced neuronal apoptosis. Int J Neurosci. 2013; 123: 155-162. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23134425
  39. Walter F, Schmid J, Dussmann H, Concannon CG, Prehn JH et al. Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival. Cell Death Differ. 2015; 22: 1502-1516. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25633195
  40. Wu CH, Giampetruzzi A, Tran H, Fallini C, Gao FB et al. A Drosophila model of ALS reveals a partial loss of function of causative human PFN1 mutants. Hum Mol Genet. 2017; 26: 2146-2155. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28379367

Figures:

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More