Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease


Autoři: Victoria Schiffer aff001;  Estibaliz Santiago-Mujika aff001;  Stefanie Flunkert aff001;  Staffan Schmidt aff002;  Martina Farcher aff001;  Tina Loeffler aff001;  Irene Schilcher aff001;  Maria Posch aff001;  Joerg Neddens aff001;  Ying Sun aff003;  Jan Kehr aff002;  Birgit Hutter-Paier aff001
Působiště autorů: QPS Austria GmbH, Neuropharmacology, Grambach, Austria aff001;  Pronexus Analytical AB, Bromma, Sweden aff002;  Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America aff003;  Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227077

Souhrn

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.

Klíčová slova:

Animal models of disease – Cerebellum – Hippocampus – Macrophages – Mouse models – Spleen – Thymus – White blood cells


Zdroje

1. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. The New England journal of medicine. 2009;361(17):1651–61. Epub 2009/10/23. doi: 10.1056/NEJMoa0901281 19846850; PubMed Central PMCID: PMC2856322.

2. Goker-Alpan O, Stubblefield BK, Giasson BI, Sidransky E. Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. Acta neuropathologica. 2010;120(5):641–9. Epub 2010/09/15. doi: 10.1007/s00401-010-0741-7 20838799; PubMed Central PMCID: PMC3352317.

3. Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. International journal of molecular sciences. 2017;18(2). Epub 2017/02/22. doi: 10.3390/ijms18020441 28218669; PubMed Central PMCID: PMC5343975.

4. Weiss K, Gonzalez A, Lopez G, Pedoeim L, Groden C, Sidransky E. The clinical management of Type 2 Gaucher disease. Molecular genetics and metabolism. 2015;114(2):110–22. Epub 2014/12/02. doi: 10.1016/j.ymgme.2014.11.008 25435509; PubMed Central PMCID: PMC4312716.

5. Sun Y, Qi X, Witte DP, Ponce E, Kondoh K, Quinn B, et al. Prosaposin: threshold rescue and analysis of the "neuritogenic" region in transgenic mice. Molecular genetics and metabolism. 2002;76(4):271–86. Epub 2002/09/05. doi: 10.1016/s1096-7192(02)00114-2 12208132.

6. Fujita N, Suzuki K, Vanier MT, Popko B, Maeda N, Klein A, et al. Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids. Human molecular genetics. 1996;5(6):711–25. Epub 1996/06/01. doi: 10.1093/hmg/5.6.711 8776585.

7. Tybulewicz VL, Tremblay ML, LaMarca ME, Willemsen R, Stubblefield BK, Winfield S, et al. Animal model of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase gene. Nature. 1992;357(6377):407–10. Epub 1992/06/04. doi: 10.1038/357407a0 1594045.

8. Sidransky E, Sherer DM, Ginns EI. Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene. Pediatric research. 1992;32(4):494–8. Epub 1992/10/01. doi: 10.1203/00006450-199210000-00023 1437405.

9. Liu Y, Suzuki K, Reed JD, Grinberg A, Westphal H, Hoffmann A, et al. Mice with type 2 and 3 Gaucher disease point mutations generated by a single insertion mutagenesis procedure. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(5):2503–8. Epub 1998/04/16. PubMed Central PMCID: PMC19391. doi: 10.1073/pnas.95.5.2503 9482915

10. Xu YH, Quinn B, Witte D, Grabowski GA. Viable mouse models of acid beta-glucosidase deficiency: the defect in Gaucher disease. The American journal of pathology. 2003;163(5):2093–101. Epub 2003/10/28. doi: 10.1016/s0002-9440(10)63566-3 14578207; PubMed Central PMCID: PMC1892407.

11. Sun Y, Quinn B, Witte DP, Grabowski GA. Gaucher disease mouse models: point mutations at the acid beta-glucosidase locus combined with low-level prosaposin expression lead to disease variants. Journal of lipid research. 2005;46(10):2102–13. Epub 2005/08/03. doi: 10.1194/jlr.M500202-JLR200 16061944.

12. Rolfs A, Giese AK, Grittner U, Mascher D, Elstein D, Zimran A, et al. Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of Gaucher disease patients. PloS one. 2013;8(11):e79732. Epub 2013/11/28. doi: 10.1371/journal.pone.0079732 24278166; PubMed Central PMCID: PMC3835853.

13. Xu YH, Sun Y, Ran H, Quinn B, Witte D, Grabowski GA. Accumulation and distribution of alpha-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Molecular genetics and metabolism. 2011;102(4):436–47. Epub 2011/01/25. doi: 10.1016/j.ymgme.2010.12.014 21257328; PubMed Central PMCID: PMC3059359.

14. Rabl R, Horvath A, Breitschaedel C, Flunkert S, Roemer H, Hutter-Paier B. Quantitative evaluation of orofacial motor function in mice: The pasta gnawing test, a voluntary and stress-free behavior test. Journal of neuroscience methods. 2016;274:125–30. Epub 2016/11/05. doi: 10.1016/j.jneumeth.2016.10.006 27746230.

15. Rabl R, Breitschaedel C, Flunkert S, Duller S, Amschl D, Neddens J, et al. Early start of progressive motor deficits in Line 61 alpha-synuclein transgenic mice. BMC neuroscience. 2017;18(1):22. Epub 2017/02/02. doi: 10.1186/s12868-017-0341-8 28143405; PubMed Central PMCID: PMC5282838.

16. Wong K, Sidransky E, Verma A, Mixon T, Sandberg GD, Wakefield LK, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Molecular genetics and metabolism. 2004;82(3):192–207. Epub 2004/07/06. doi: 10.1016/j.ymgme.2004.04.011 15234332.

17. Verity MA, Montasir M. Infantile Gaucher's disease: neuropathology, acid hydrolase activities and negative staining observations. Neuropadiatrie. 1977;8(1):89–100. Epub 1977/02/01. doi: 10.1055/s-0028-1091508 576736.

18. Xu YH, Xu K, Sun Y, Liou B, Quinn B, Li RH, et al. Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice. Human molecular genetics. 2014;23(15):3943–57. Epub 2014/03/07. doi: 10.1093/hmg/ddu105 24599400; PubMed Central PMCID: PMC4082362.

19. Choi JH, Stubblefield B, Cookson MR, Goldin E, Velayati A, Tayebi N, et al. Aggregation of alpha-synuclein in brain samples from subjects with glucocerebrosidase mutations. Molecular genetics and metabolism. 2011;104(1–2):185–8. Epub 2011/07/12. doi: 10.1016/j.ymgme.2011.06.008 21742527; PubMed Central PMCID: PMC3352315.

20. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146(1):37–52. Epub 2011/06/28. doi: 10.1016/j.cell.2011.06.001 21700325; PubMed Central PMCID: PMC3132082.

21. Abdelwahab M, Potegal M, Shapiro EG, Nestrasil I. Previously unrecognized behavioral phenotype in Gaucher disease type 3. Neurology Genetics. 2017;3(3):e158. Epub 2017/06/22. doi: 10.1212/NXG.0000000000000158 28634598; PubMed Central PMCID: PMC5458667.

22. Tylki-Szymanska A, Vellodi A, El-Beshlawy A, Cole JA, Kolodny E. Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. Journal of inherited metabolic disease. 2010;33(4):339–46. Epub 2010/01/20. doi: 10.1007/s10545-009-9009-6 20084461.

23. Tajima A, Yokoi T, Ariga M, Ito T, Kaneshiro E, Eto Y, et al. Clinical and genetic study of Japanese patients with type 3 Gaucher disease. Molecular genetics and metabolism. 2009;97(4):272–7. Epub 2009/06/02. doi: 10.1016/j.ymgme.2009.05.001 19481486.

24. Sorrentino P, Barbato A, Del Gaudio L, Rucco R, Varriale P, Sibilio M, et al. Impaired gait kinematics in type 1 Gaucher's Disease. Journal of Parkinson's disease. 2016;6(1):191–5. Epub 2016/01/13. doi: 10.3233/JPD-150660 26756743.

25. Abdelwahab M, Blankenship D, Schiffmann R. Long-term follow-up and sudden unexpected death in Gaucher disease type 3 in Egypt. Neurology Genetics. 2016;2(2):e55. Epub 2016/04/29. doi: 10.1212/NXG.0000000000000055 27123474; PubMed Central PMCID: PMC4830203.

26. Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Archives of internal medicine. 2000;160(18):2835–43. Epub 2000/10/12. doi: 10.1001/archinte.160.18.2835 11025794.

27. Amir G, Ron N. Pulmonary pathology in Gaucher's disease. Hum Pathol. 1999;30(6):666–70. Epub 1999/06/22. doi: 10.1016/s0046-8177(99)90092-8 10374775.

28. Nishino M, Ashiku SK, Kocher ON, Thurer RL, Boiselle PM, Hatabu H. The thymus: a comprehensive review. Radiographics: a review publication of the Radiological Society of North America, Inc. 2006;26(2):335–48. Epub 2006/03/22. doi: 10.1148/rg.262045213 16549602.

29. Sun Y, Liou B, Ran H, Skelton MR, Williams MT, Vorhees CV, et al. Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. Human molecular genetics. 2010;19(6):1088–97. Epub 2010/01/06. doi: 10.1093/hmg/ddp580 20047948; PubMed Central PMCID: PMC2830832.

30. Hamler R, Brignol N, Clark SW, Morrison S, Dungan LB, Chang HH, et al. Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease. Analytical chemistry. 2017;89(16):8288–95. Epub 2017/07/08. doi: 10.1021/acs.analchem.7b01442 28686011.

31. Jones EE, Zhang W, Zhao X, Quiason C, Dale S, Shahidi-Latham S, et al. Tissue Localization of Glycosphingolipid Accumulation in a Gaucher Disease Mouse Brain by LC-ESI-MS/MS and High-Resolution MALDI Imaging Mass Spectrometry. SLAS discovery: advancing life sciences R & D. 2017;22(10):1218–28. Epub 2017/07/18. doi: 10.1177/2472555217719372 28714776.

32. Fuller M, Szer J, Stark S, Fletcher JM. Rapid, single-phase extraction of glucosylsphingosine from plasma: A universal screening and monitoring tool. Clinica chimica acta; international journal of clinical chemistry. 2015;450:6–10. Epub 2015/08/02. doi: 10.1016/j.cca.2015.07.026 26232157.

33. Murugesan V, Chuang WL, Liu J, Lischuk A, Kacena K, Lin H, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. American journal of hematology. 2016;91(11):1082–9. Epub 2016/10/21. doi: 10.1002/ajh.24491 27441734; PubMed Central PMCID: PMC5234703.

34. Burrow TA, Sun Y, Prada CE, Bailey L, Zhang W, Brewer A, et al. CNS, lung, and lymph node involvement in Gaucher disease type 3 after 11 years of therapy: clinical, histopathologic, and biochemical findings. Molecular genetics and metabolism. 2015;114(2):233–41. Epub 2014/09/16. doi: 10.1016/j.ymgme.2014.08.011 25219293; PubMed Central PMCID: PMC4312736.

35. Vitner EB, Farfel-Becker T, Eilam R, Biton I, Futerman AH. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher's disease. Brain: a journal of neurology. 2012;135(Pt 6):1724–35. Epub 2012/05/09. doi: 10.1093/brain/aws095 22566609.

36. Farfel-Becker T, Vitner EB, Pressey SN, Eilam R, Cooper JD, Futerman AH. Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease. Human molecular genetics. 2011;20(7):1375–86. Epub 2011/01/22. doi: 10.1093/hmg/ddr019 21252206.

37. Ginns EI, Mak SK, Ko N, Karlgren J, Akbarian S, Chou VP, et al. Neuroinflammation and alpha-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction. Molecular genetics and metabolism. 2014;111(2):152–62. Epub 2014/01/07. doi: 10.1016/j.ymgme.2013.12.003 24388731.

38. Ran C, Brodin L, Forsgren L, Westerlund M, Ramezani M, Gellhaar S, et al. Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden. Neurobiology of aging. 2016;45:212 e5–e11. Epub 2016/06/04. doi: 10.1016/j.neurobiolaging.2016.04.022 27255555; PubMed Central PMCID: PMC4982543.

39. Li Y, Li P, Liang H, Zhao Z, Hashimoto M, Wei J. Gaucher-Associated Parkinsonism. Cellular and molecular neurobiology. 2015;35(6):755–61. Epub 2015/03/31. doi: 10.1007/s10571-015-0176-8 25820783; PubMed Central PMCID: PMC4502293.

40. Vilageliu L, Grinberg D. Involvement of Gaucher Disease Mutations in Parkinson Disease. Curr Protein Pept Sci. 2017;18(7):758–64. Epub 2016/03/12. doi: 10.2174/1389203717666160311115956 26965692.

41. Maor G, Rapaport D, Horowitz M. The effect of mutant GBA1 on accumulation and aggregation of alpha-synuclein. Human molecular genetics. 2019. Epub 2019/01/08. doi: 10.1093/hmg/ddz005 30615125.

42. Taguchi YV, Liu J, Ruan J, Pacheco J, Zhang X, Abbasi J, et al. Glucosylsphingosine Promotes alpha-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2017;37(40):9617–31. Epub 2017/08/30. doi: 10.1523/JNEUROSCI.1525-17.2017 28847804; PubMed Central PMCID: PMC5628407.

43. Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, et al. Acid beta-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Annals of neurology. 2011;69(6):940–53. Epub 2011/04/08. doi: 10.1002/ana.22400 21472771.

44. Pampols T, Pineda M, Giros ML, Ferrer I, Cusi V, Chabas A, et al. Neuronopathic juvenile glucosylceramidosis due to sap-C deficiency: clinical course, neuropathology and brain lipid composition in this Gaucher disease variant. Acta neuropathologica. 1999;97(1):91–7. Epub 1999/02/04. doi: 10.1007/s004010050960 9930900.

45. Conradi N, Kyllerman M, Mansson JE, Percy AK, Svennerholm L. Late-infantile Gaucher disease in a child with myoclonus and bulbar signs: neuropathological and neurochemical findings. Acta neuropathologica. 1991;82(2):152–7. Epub 1991/01/01. doi: 10.1007/bf00293959 1718128.

46. Yoneshige A, Suzuki K, Suzuki K, Matsuda J. A mutation in the saposin C domain of the sphingolipid activator protein (Prosaposin) gene causes neurodegenerative disease in mice. Journal of neuroscience research. 2010;88(10):2118–34. Epub 2010/02/23. doi: 10.1002/jnr.22371 20175216.

47. Sun Y, Ran H, Zamzow M, Kitatani K, Skelton MR, Williams MT, et al. Specific saposin C deficiency: CNS impairment and acid beta-glucosidase effects in the mouse. Human molecular genetics. 2010;19(4):634–47. Epub 2009/12/18. doi: 10.1093/hmg/ddp531 20015957; PubMed Central PMCID: PMC2807372.

48. Mizukami H, Mi Y, Wada R, Kono M, Yamashita T, Liu Y, et al. Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage. The Journal of clinical investigation. 2002;109(9):1215–21. Epub 2002/05/08. doi: 10.1172/JCI14530 11994410; PubMed Central PMCID: PMC150961.


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