Developmental expression of human tau in Drosophila melanogaster glial cells induces motor deficits and disrupts maintenance of PNS axonal integrity, without affecting synapse formation

Autoři: Enrico M. Scarpelli aff001;  Van Y. Trinh aff003;  Zarrin Tashnim aff003;  Jacob L. Krans aff004;  Lani C. Keller aff001;  Kenneth J. Colodner aff003
Působiště autorů: Frank H. Netter, M.D. School of Medicine, Quinnipiac University, North Haven, CT, United States of America aff001;  Department of Biological Sciences, Quinnipiac University, Hamden, CT, United States of America aff002;  Program in Neuroscience and Behavior, Mount Holyoke College, South Hadley, MA, United States of America aff003;  Department of Neuroscience, Western New England University, Springfield, MA, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0226380


Tauopathies are a class of neurodegenerative diseases characterized by the abnormal phosphorylation and accumulation of the microtubule-associated protein, tau, in both neuronal and glial cells. Though tau pathology in glial cells is a prominent feature of many of these disorders, the pathological contribution of these lesions to tauopathy pathogenesis remains largely unknown. Moreover, while tau pathology is predominantly found in the central nervous system, a role for tau in the cells of the peripheral nervous system has been described, though not well characterized. To investigate the effects of glial tau expression on the development and maintenance of the peripheral nervous system, we utilized a Drosophila melanogaster model of tauopathy that expresses human wild-type tau in glial cells during development. We found that glial tau expression during development results in larval locomotor deficits and organismal lethality at the pupal stage, without affecting larval neuromuscular junction synapse development or post-synaptic amplitude. There was, however, a significant decrease in the decay time of synaptic potentials upon repeated stimulation of the motoneuron. Behavioral abnormalities were accompanied by glial cell death, disrupted maintenance of glial-axonal integrity, and the abnormal accumulation of the presynaptic protein, Bruchpilot, in peripheral nerve axons. Together, these data demonstrate that human tau expression in Drosophila glial cells does not affect neuromuscular junction synapse formation during development, but is deleterious to the maintenance of glial-axonal interactions in the peripheral nervous system.

Klíčová slova:

Drosophila melanogaster – Apoptosis – Central nervous system – Synapses – Nerves – Larvae – Phosphorylation – Cell disruption


1. Ballatore C, Lee VM-Y, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8: 663–672. doi: 10.1038/nrn2194 17684513

2. Chin SS, Goldman JE. Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol. 1996;55: 499–508. doi: 10.1097/00005072-199605000-00001 8627339

3. Kahlson MA, Colodner KJ. Glial Tau Pathology in Tauopathies: Functional Consequences. J Exp Neurosci. 2015;9: 43–50. doi: 10.4137/JEN.S25515 26884683

4. Barres BA. The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease. Neuron. 2008;60: 430–40. doi: 10.1016/j.neuron.2008.10.013 18995817

5. Zuchero JB, Barres BA. Glia in mammalian development and disease. Development. 2015;142: 3805–3809. doi: 10.1242/dev.129304 26577203

6. Forman MS, Lal D, Zhang B, Dabir D V, Swanson E, Lee VM-Y, et al. Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration. J Neurosci. 2005;25: 3539–3550. doi: 10.1523/JNEUROSCI.0081-05.2005 15814784

7. Higuchi M, Zhang B, Forman M, Yoshiyama Y, Trojanowski J, Lee V. Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies. J Neurosci. 2005;25: 9434–9443. doi: 10.1523/JNEUROSCI.2691-05.2005 16221853

8. Leyns CEG, Holtzman DM. Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017;12: 50. doi: 10.1186/s13024-017-0192-x 28662669

9. Dugger BN, Hoffman BR, Scroggins A, Serrano GE, Adler CH, Shill HA, et al. Tau immunoreactivity in peripheral tissues of human aging and select tauopathies. Neurosci Lett. 2019;696: 132–139. doi: 10.1016/j.neulet.2018.12.031 30579993

10. Couchie D, Mavilia C, Georgieff IS, Liem RK, Shelanski ML, Nunez J. Primary structure of high molecular weight tau present in the peripheral nervous system. Proc Natl Acad Sci. 1992;89: 4378–4381. doi: 10.1073/pnas.89.10.4378 1374898

11. Goedert M, Spillantini MG, Crowther RA. Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system. Proc Natl Acad Sci. 1992;89: 1983–1987. doi: 10.1073/pnas.89.5.1983 1542696

12. Sotiropoulos I, Galas MC, Silva JM, Skoulakis E, Wegmann S, Maina MB, et al. Atypical, non-standard functions of the microtubule associated Tau protein. Acta Neuropathol Commun. 2017;5: 91. doi: 10.1186/s40478-017-0489-6 29187252

13. Lopes S, Lopes A, Pinto V, Guimarães MR, Sardinha VM, Duarte-Silva S, et al. Absence of Tau triggers age-dependent sciatic nerve morphofunctional deficits and motor impairment. Aging Cell. 2016;15: 208–216. doi: 10.1111/acel.12391 26748966

14. Merchán-Rubira J, Sebastián-Serrano Á, Díaz-Hernández M, Avila J, Hernández F. Peripheral nervous system effects in the PS19 tau transgenic mouse model of tauopathy. Neurosci Lett. 2019;698: 204–208. doi: 10.1016/j.neulet.2019.01.031 30677432

15. Higuchi M, Ishihara T, Zhang B, Hong M, Andreadis A, Trojanowski JQ, et al. Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration. Neuron. 2002;35: 433–446. doi: 10.1016/s0896-6273(02)00789-4 12165467

16. LoPresti P. Tau in Oligodendrocytes Takes Neurons in Sickness and in Health. Int J Mol Sci. 2018;19: E2408. doi: 10.3390/ijms19082408 30111714

17. Allen NJ, Barres BA. Neuroscience: Glia—more than just brain glue. Nature. 2009;457: 675–7. doi: 10.1038/457675a 19194443

18. Freeman MR. Drosophila central nervous system glia. Cold Spring Harb Perspect Biol. 2015;7: a020552. doi: 10.1101/cshperspect.a020552 25722465

19. Muthukumar AK, Stork T, Freeman MR. Activity-dependent regulation of astrocyte GAT levels during synaptogenesis. Nat Neurosci. 2014;17: 1340–1350. doi: 10.1038/nn.3791 25151265

20. Yildirim K, Petri J, Kottmeier R, Klämbt C. Drosophila glia: Few cell types and many conserved functions. Glia. 2019;67: 5–26. doi: 10.1002/glia.23459 30443934

21. Brink DL, Gilbert M, Xie X, Petley-Ragan L, Auld VJ. Glial processes at the Drosophila larval neuromuscular junction match synaptic growth. PLoS One. 2012;7: e37876. doi: 10.1371/journal.pone.0037876 22666403

22. Matzat T, Sieglitz F, Kottmeier R, Babatz F, Engelen D, Klambt C. Axonal wrapping in the Drosophila PNS is controlled by glia-derived neuregulin homolog Vein. Development. 2015;142: 1336–1345. doi: 10.1242/dev.116616 25758464

23. Colodner KJ, Feany MB. Glial Fibrillary Tangles and JAK/STAT-Mediated Glial and Neuronal Cell Death in a Drosophila Model of Glial Tauopathy. J Neurosci. 2010;30: 16102–16113. doi: 10.1523/JNEUROSCI.2491-10.2010 21123557

24. McGuire SE, Mao Z, Davis RL. Spatiotemporal Gene Expression Targeting with the TARGET and Gene-Switch Systems in Drosophila. Sci STKE. 2004;2004: pl6. doi: 10.1126/stke.2202004pl6 14970377

25. Heckscher ES, Lockery SR, Doe CQ. Characterization of Drosophila larval crawling at the level of organism, segment, and somatic body wall musculature. J Neurosci. 2012;32: 12460–12471. doi: 10.1523/JNEUROSCI.0222-12.2012 22956837

26. Massaro CM, Pielage J, Davis GW. Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton. J Cell Biol. 2009;187: 101–117. doi: 10.1083/jcb.200903166 19805631

27. Johnson EL, Fetter RD, Davis GW. Negative regulation of active zone assembly by a newly identified SR protein kinase. PLoS Biol. 2009;7: e1000193. doi: 10.1371/journal.pbio.1000193 19771148

28. Rio DC, Ares M, Hannon GJ, Nilsen TW. Purification of RNA using TRIzol (TRI Reagent). Cold Spring Harb Protoc. 2010;2010: pdb.prot5439. doi: 10.1101/pdb.prot5439 20516177

29. Feng Y, Ueda A, Wu CF. A modified minimal hemolymph-like solution, HL3.1, for physiological recordings at the neuromuscular junctions of normal and mutant Drosophila larvae. J Neurogenet. 2004;18: 377–402. doi: 10.1080/01677060490894522 15763995

30. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118: 401–415. 8223268

31. Duncan JE, Lytle NK, Zuniga A, Goldstein LS. The Microtubule Regulatory Protein Stathmin Is Required to Maintain the Integrity of Axonal Microtubules in Drosophila. PLoS One. 2013;8: e68324. doi: 10.1371/journal.pone.0068324 23840848

32. Horiuchi D, Barkus R V., Pilling AD, Gassman A, Saxton WM. APLIP1, a kinesin binding JIP-1/JNK scaffold protein, influences the axonal transport of both vesicles and mitochondria in Drosophila. Curr Biol. 2005;15: 2137–2141. doi: 10.1016/j.cub.2005.10.047 16332540

33. Jan LY, Jan YN. Antibodies to horseradish peroxidase as specific neuronal markers in Drosophila and in grasshopper embryos. Proc Natl Acad Sci. 1982;79: 2700–2704. doi: 10.1073/pnas.79.8.2700 6806816

34. Williams DW, Kondo S, Krzyzanowska A, Hiromi Y, Truman JW. Local caspase activity directs engulfment of dendrites during pruning. Nat Neurosci. 2006;9: 1234–1236. doi: 10.1038/nn1774 16980964

35. Bardai FH, Wang L, Mutreja Y, Yenjerla M, Gamblin TC, Feany MB. A conserved cytoskeletal signaling cascade mediates neurotoxicity of FTDP-17 tau mutations in vivo. J Neurosci. 2018;38: 108–119. doi: 10.1523/JNEUROSCI.1550-17.2017 29138281

36. Wang L, Hagemann TL, Messing A, Feany MB. An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease. J Neurosci. 2016;36: 1445–1455. doi: 10.1523/JNEUROSCI.0256-15.2016 26843629

37. Ferrer I, Lopez-Gonzalez I, Carmona M, Arregui L, Dalfo E, Torrejon-Escribano B, et al. Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J Neuropathol Exp Neurol. 2014;73: 81–97. doi: 10.1097/NEN.0000000000000030 24335532

38. Sepp KJ, Auld VJ. Reciprocal interactions between neurons and glia are required for Drosophila peripheral nervous system development. J Neurosci. 2003;23: 8221–8230. doi: 10.1523/JNEUROSCI.23-23-08221.2003 12967983

39. Xie X, Auld VJ. Integrins are necessary for the development and maintenance of the glial layers in the Drosophila peripheral nerve. Development. 2011;138: 3813–3822. doi: 10.1242/dev.064816 21828098

40. Wagh DA, Rasse TM, Asan E, Hofbauer A, Schwenkert I, Dürrbeck H, et al. Bruchpilot, a protein with homology to ELKS/CAST, is required for structural integrity and function of synaptic active zones in Drosophila. Neuron. 2006;49: 833–844. doi: 10.1016/j.neuron.2006.02.008 16543132

41. Kovacs GG. Invited review: Neuropathology of tauopathies: Principles and practice. Neuropathol Appl Neurobiol. 2015;41: 3–23. doi: 10.1111/nan.12208 25495175

42. Dugger BN, Whiteside CM, Maarouf CL, Walker DG, Beach TG, Sue LI, et al. The presence of select tau species in human peripheral tissues and their relation to Alzheimer’s disease. J Alzheimer’s Dis. 2016;51: 345–356. doi: 10.3233/JAD-150859 26890756

43. Kawasaki H, Murayama S, Tomonaga M, Izumiyama N, Shimada H. Neurofibrillary tangles in human upper cervical ganglia—Morphological study with immunohistochemistry and electron microscopy. Acta Neuropathol. 1987;75: 156–159. doi: 10.1007/bf00687076 3434223

44. Nishimura M, Namba Y, Ikeda K, Akiguchi I, Oda M. Neurofibrillary tangles in the neurons of spinal dorsal root ganglia of patients with progressive supranuclear palsy. Acta Neuropathol. 1993;85: 453–457. doi: 10.1007/bf00230481 8388145

45. Wakabayashi K, Mori F, Tanji K, Orimo S, Takahashi H. Involvement of the peripheral nervous system in synucleinopathies, tauopathies and other neurodegenerative proteinopathies of the brain. Acta Neuropathol. 2010;120: 1–12. doi: 10.1007/s00401-010-0706-x 20532896

46. de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, et al. Propagation of Tau Pathology in a Model of Early Alzheimer’s Disease. Neuron. 2012;73: 685–697. doi: 10.1016/j.neuron.2011.11.033 22365544

47. Narasimhan S, Guo JL, Changolkar L, Stieber A, McBride JD, Silva L V., et al. Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain. J Neurosci. 2017;37: 11406–11423. doi: 10.1523/JNEUROSCI.1230-17.2017 29054878

48. Frost B, Götz J, Feany MB. Connecting the dots between tau dysfunction and neurodegeneration. Trends Cell Biol. 2015;25: 46–53. doi: 10.1016/j.tcb.2014.07.005 25172552

49. Chee FC, Mudher A, Cuttle MF, Newman TA, MacKay D, Lovestone S, et al. Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Neurobiol Dis. 2005;20: 918–928. doi: 10.1016/j.nbd.2005.05.029 16023860

50. Folwell J, Cowan CM, Ubhi KK, Shiabh H, Newman TA, Shepherd D, et al. Aβ exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer’s disease. Exp Neurol. 2010;223: 401–409. doi: 10.1016/j.expneurol.2009.09.014 19782075

51. Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, Hyman BT, et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol. 2007;9: 139–148. doi: 10.1038/ncb1528 17187063

52. Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol. 2006;16: 230–241. doi: 10.1016/j.cub.2005.12.042 16461276

53. Mudher A, Shepherd D, Newman TA, Mildren P, Jukes JP, Squire A, et al. GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry. 2004;9: 522–530. doi: 10.1038/ 14993907

54. Steinhilb ML, Dias-Santagata D, Mulkearns EE, Shulman JM, Biernat J, Mandelkow EM, et al. S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila. J Neurosci Res. 2007;85: 1271–1278. doi: 10.1002/jnr.21232 17335084

55. Sealey MA, Vourkou E, Cowan CM, Bossing T, Quraishe S, Grammenoudi S, et al. Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy. Neurobiol Dis. 2017;105: 74–83. doi: 10.1016/j.nbd.2017.05.003 28502805

56. Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, et al. Tauopathy in Drosophila: Neurodegeneration without neurofibrillary tangles. Science (80-). 2001;293: 711–714. doi: 10.1126/science.1062382 11408621

57. Kadas D, Papanikolopoulou K, Xirou S, Consoulas C, Skoulakis EMC. Human Tau isoform-specific presynaptic deficits in a Drosophila Central Nervous System circuit. Neurobiol Dis. 2019;124: 311–321. doi: 10.1016/j.nbd.2018.12.004 30529489

58. Grammenoudi S, Kosmidis S, Skoulakis EM. Cell type-specific processing of human Tau proteins in Drosophila. FEBS Lett. 2006;580: 4602–4606. doi: 10.1016/j.febslet.2006.07.045 16875690

59. Arbouzova NI, Zeidler MP. JAK/STAT signalling in Drosophila: insights into conserved regulatory and cellular functions. Development. 2006;133: 2605–2616. doi: 10.1242/dev.02411 16794031

60. Doherty J, Sheehan AE, Bradshaw R, Fox AN, Lu TY, Freeman MR. PI3K Signaling and Stat92E Converge to Modulate Glial Responsiveness to Axonal Injury. PLoS Biol. 2014;12: e1001985. doi: 10.1371/journal.pbio.1001985 25369313

61. Sepp KJ, Schulte J, Auld VJ. Developmental Dynamics of Peripheral Glia in Drosophila melanogaster. Glia. 2000;30: 122–133. doi: 10.1002/(sici)1098-1136(200004)30:2<122::aid-glia2>;2-b 10719354

62. Halter DA, Urban J, Rickert C, Ner SS, Ito K, Travers AA, et al. The homeobox gene repo is required for the differentiation and maintenance of glia function in the embryonic nervous system of Drosophila melanogaster. Development. 1995;121: 317–332. 7768175

63. Keller LC, Cheng L, Locke CJ, Müller M, Fetter RD, Davis GW. Glial-derived prodegenerative signaling in the drosophila neuromuscular system. Neuron. 2011;72: 760–775. doi: 10.1016/j.neuron.2011.09.031 22153373

64. Meyer S, Schmidt I, Klämbt C. Glia ECM interactions are required to shape the Drosophila nervous system. Mech Dev. 2014;133: 105–116. doi: 10.1016/j.mod.2014.05.003 24859129

65. Nave K-A, Trapp BD. Axon-Glial Signaling and the Glial Support of Axon Function. Annu Rev Neurosci. 2008;31: 535–561. doi: 10.1146/annurev.neuro.30.051606.094309 18558866

66. Barber KR, Tanquary J, Bush K, Shaw A, Woodson M, Sherman M, et al. Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase. PLoS Genet. 2017;13: e1006822. doi: 10.1371/journal.pgen.1006822 28562608

67. Barber KR, Hruska M, Bush KM, Martinez JA, Fei H, Levitan IB, et al. Levels of Par-1 kinase determine the localization of Bruchpilot at the Drosophila neuromuscular junction synapses. Sci Rep. 2018;8: 16099. doi: 10.1038/s41598-018-34250-9 30382129

68. Wairkar YP, Trivedi D, Natarajan R, Barnes K, Dolores L, Cho P. CK2α regulates the transcription of BRP in Drosophila. Dev Biol. 2013;384: 53–64. doi: 10.1016/j.ydbio.2013.09.025 24080510

69. Dolan PJ, Johnson G V. The role of tau kinases in Alzheimer’s disease. Curr Opin Drug Discov Devel. 2010;13: 595–603. 20812151

70. Stork T, Engelen D, Krudewig A, Silies M, Bainton RJ, Klambt C. Organization and Function of the Blood Brain Barrier in Drosophila. J Neurosci. 2008;28: 587–597. doi: 10.1523/JNEUROSCI.4367-07.2008 18199760

Článok vyšiel v časopise


2019 Číslo 12