PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease

English version

Autoři: Alex G. Nackenoff ^aff001; Timothy J. Hohman ^aff001; Sarah M. Neuner ^aff003; Carolyn S. Akers ^aff001; Nicole C. Weitzel ^aff001; Alena Shostak ^aff001; Shawn M. Ferguson ^aff004; Bret Mobley ^aff005; David A. Bennett ^aff006; Julie A. Schneider ^aff006; Angela L. Jefferson ^aff001; Catherine C. Kaczorowski ^aff003; Matthew S. Schrag ^aff001
Působiště autorů: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ^aff001; Vanderbilt Memory and Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ^aff002; The Jackson Laboratory, Bar Harbor, Maine, United States of America ^aff003; Department of Cell Biology, Yale University, New Haven, Connecticut, United States of America ^aff004; Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ^aff005; Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America ^aff006
Vyšlo v časopise: PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer’s disease. PLoS Genet 17(4): e1009406. doi:10.1371/journal.pgen.1009406
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009406

Souhrn

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with β-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both β-amyloid pathology and cognition.

Klíčová slova:

Alzheimer's disease – Lysosomes – Medical risk factors – Mouse models – Neurites – Phospholipases – Small interfering RNA – Transfection

Zdroje

1. Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature. 2013;505 : 550–554. doi: 10.1038/nature12825 24336208

2. Brown HA, Thomas PG, Lindsley CW. Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nat Rev Drug Discov. 2017;16 : 351–367. doi: 10.1038/nrd.2016.252 28209987

3. Gavin AL, Huang D, Huber C, Mårtensson A, Tardif V, Skog PD, et al. PLD3 and PLD4 are single stranded acid exonucleases that regulate endosomal nucleic acid sensing. Nat Immunol. 2018;19 : 942–953. doi: 10.1038/s41590-018-0179-y 30111894

4. Ipsaro JJ, Haase AD, Knott SR, Joshua-Tor L, Hannon GJ. The structural biochemistry of Zucchini implicates it as a nuclease in piRNA biogenesis. Nature. 2012;491 : 279–283. doi: 10.1038/nature11502 23064227

5. Saito M, Kanfer J. Solubilization and properties of a membrane-bound enzyme from rat brain catalyzing a base-exchange reaction. Biochem Biophys Res Commun. 1973;53 : 391–398. doi: 10.1016/0006-291x(73)90674-8 4736814

6. Gonzalez AC, Stroobants S, Reisdorf P, Gavin AL, Nemazee D, Schwudke D, et al. PLD3 and spinocerebellar ataxia. Brain. 2018;141: e78–e78. doi: 10.1093/brain/awy258 30312375

7. Pederson KM, Finsen B, Celis JE, Jensen NA. Expression of a movel murine phospholiase D homolog coincides with late neuronal development in the forebrain. J Biol Chem 1998;273(47):31494–31504. doi: 10.1074/jbc.273.47.31494 9813063

8. Fazzari P, Horre K, Arranz AM, Frigerio CS, Saito T, Saido TC, et al. PLD3 gene and processing of APP. Nature. 2017;541: E1–E2. doi: 10.1038/nature21030 28128235

9. Hooli BV, Lill CM, Mullin K, Qiao D, Lange C, Bertram L, et al. PLD3 gene variants and Alzheimer’s disease. Nature. 2015;520: E7–8. doi: 10.1038/nature14040 25832413

10. Lambert J-C, Grenier-Boley B, Bellenguez C, Pasquier F, Campion D, Dartigues J-F, et al. PLD3 and sporadic Alzheimer’s disease risk. Nature. 2015;520: E1. doi: 10.1038/nature14036 25832408

11. Heilmann S, Drichel D, Clarimon J, Fernández V, Lacour A, Wagner H, et al. PLD3 in non-familial Alzheimer’s disease. Nature. 2015;520: E3–5. doi: 10.1038/nature14039 25832411

12. van der Lee SJ, Holstege H, Wong TH, Jakobsdottir J, Bis JC, Chouraki V, et al. PLD3 variants in population studies. Nature. 2015;520: E2–3. doi: 10.1038/nature14038 25832410

13. Engelman CD, Darst BF, Bilgel M, Vasiljevic E, Koscik RL, Jedynak BM, et al. The effect of rare variants in TREM2 and PLD3 on longitudinal cognitive function in the Wisconsin Registry for Alzheimer’s Prevention. Neurobiology of Aging. 2017. doi: 10.1016/j.neurobiolaging.2017.12.025 29395285

14. Neuner SM, Heuer SE, Huentelman MJ, O’Connell KMS, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer’s Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019;101 : 399–411.e5. doi: 10.1016/j.neuron.2018.11.040 30595332

15. Neuner SM, Hohman TJ, Richholt R, Bennett DA, Schneider JA, Jager PLD, et al. Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience. bioRxiv. 2017; 225714. doi: 10.1101/225714

16. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26 : 10129–10140. doi: 10.1523/JNEUROSCI.1202-06.2006 17021169

17. Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS. Overview and findings from the religious orders study. Curr Alzheimer Res. 2012;9 : 628–645. doi: 10.2174/156720512801322573 22471860

18. Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS. Overview and findings from the rush Memory and Aging Project. Curr Alzheimer Res. 2012;9 : 646–663. doi: 10.2174/156720512801322663 22471867

19. Bennett DA, Buchman AS, Boyle PA, Barnes LL, Wilson RS, Schneider JA. Religious Orders Study and Rush Memory and Aging Project. J Alzheimers Dis. 2018;64: S161–S189. doi: 10.3233/JAD-179939 29865057

20. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69 : 2197–2204. doi: 10.1212/01.wnl.0000271090.28148.24 17568013

21. Mostafavi S, Gaiteri C, Sullivan SE, White CC, Tasaki S, Xu J, et al. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease. Nat Neurosci. 2018;21 : 811–819. doi: 10.1038/s41593-018-0154-9 29802388

22. Mahoney ER, Dumitrescu L, Moore AM, Cambronero FE, Jager PLD, Koran MEI, et al. Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer’s disease. Mol Psychiatry. 2019; 1–9. doi: 10.1038/s41380-019-0458-5 31332262

23. Arvanitakis Z, Capuano AW, Leurgans SE, Buchman AS, Bennett DA, Schneider JA. The Relationship of Cerebral Vessel Pathology to Brain Microinfarcts. Brain Pathology. 2017;27 : 77–85. doi: 10.1111/bpa.12365 26844934

24. Zoe Arvanitakis, Leurgans Sue E., Barnes Lisa L., Bennett David A., Schneider Julie A. Microinfarct Pathology, Dementia, and Cognitive Systems. Stroke. 2011;42 : 722–727. doi: 10.1161/STROKEAHA.110.595082 21212395

25. Boyle PA, Yu L, Nag S, Leurgans S, Wilson RS, Bennett DA, et al. Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology. 2015;85 : 1930–1936. doi: 10.1212/WNL.0000000000002175 26537052

26. Buchman Aron S., Leurgans Sue E., Nag Sukriti, Bennett David A., Schneider Julie A. Cerebrovascular Disease Pathology and Parkinsonian Signs in Old Age. Stroke. 2011;42 : 3183–3189. doi: 10.1161/STROKEAHA.111.623462 21885844

27. Love S, Chalmers K, Ince P, Esiri M, Attems J, Jellinger K, et al. Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue. Am J Neurodegener Dis. 2014;3 : 19–32. 24754000

28. Schneider JA, Wilson RS, Cochran EJ, Bienias JL, Arnold SE, Evans DA, et al. Relation of cerebral infarctions to dementia and cognitive function in older persons. Neurology. 2003;60 : 1082–1088. doi: 10.1212/01.wnl.0000055863.87435.b2 12682310

29. Schneider JA, Boyle PA, Arvanitakis Z, Bienias JL, Bennett DA. Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Ann Neurol. 2007;62 : 59–66. doi: 10.1002/ana.21142 17503514

30. Amador-Ortiz C, Lin W-L, Ahmed Z, Personett D, Davies P, Duara R, et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol. 2007;61 : 435–445. doi: 10.1002/ana.21154 17469117

31. Wilson RS, Boyle PA, Yu L, Barnes LL, Sytsma J, Buchman AS, et al. Temporal course and pathologic basis of unawareness of memory loss in dementia. Neurology. 2015;85 : 984–991. doi: 10.1212/WNL.0000000000001935 26311746

32. Diettrich O, Mills K, Johnson AW, Hasilik A, Winchester BG. Application of magnetic chromatography to the isolation of lysosomes from fibroblasts of patients with lysosomal storage disorders. FEBS Lett. 1998;441 : 369–372. doi: 10.1016/s0014-5793(98)01578-6 9891973

33. Osisami M, Ali W, Frohman MA. A Role for Phospholipase D3 in Myotube Formation. PLOS ONE. 2012;7: e33341. doi: 10.1371/journal.pone.0033341 22428023

34. Gonzalez AC, Schweizer M, Jagdmann S, Bernreuther C, Reinheckel T, Saftig P, et al. Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes. Cell Reports. 2018;22 : 1040–1053. doi: 10.1016/j.celrep.2017.12.100 29386126

35. Demirev AV, Song H-L, Cho M-H, Cho K, Peak J-J, Yoo HJ, et al. V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function. Neurobiology of Disease. 2019 [cited 24 May 2019]. doi: 10.1016/j.nbd.2019.05.015 31121321

36. Gowrishankar S, Yuan P, Wu Y, Schrag M, Paradise S, Grutzendler J, et al. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proc Natl Acad Sci U S A. 2015;112: E3699–E3708. doi: 10.1073/pnas.1510329112 26124111

37. Puzzo D, Lee L, Palmeri A, Calabrese G, Arancio O. Behavioral assays with mouse models of Alzheimer’s disease: practical considerations and guidelines. Biochem Pharmacol. 2014;88 : 450–467. doi: 10.1016/j.bcp.2014.01.011 24462904

38. Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ. Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet. 2014;5. doi: 10.3389/fgene.2014.00088 24795750

39. Zhang DF, Fan Y, Wang D, Bi R, Zhang C, Fang Y, Yao YG. PLD3 in Alzheimer’s disease: a modest effect as revealed by updated association and expression analyses. Mol Neurobiol. 2016;53(6):4034–4045. doi: 10.1007/s12035-015-9353-5 26189833

40. Kao AW, McKay A, Singh PP, Huang EJ. Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 2017;18(6):325–333. doi: 10.1038/nrn.2017.36 28435163

41. Migdalska-Richards A, Schapira AH. The relationship between glucocerebrocidase mutations and Parkinson disease. J Neurochem 2016;139Suppl 1 : 198–215.

42. Cataldo AM, Hamilton DJ, Nixon RA. Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease. Brain Res. 1994;640 : 68–80. doi: 10.1016/0006-8993(94)91858-9 8004466

43. Satoh J, Kino Y, Yamamoto Y, Kawana N, Ishida T, Saito Y, et al. PLD3 is accumulated on neuritic plaques in Alzheimer’s disease brains. Alzheimer’s Research & Therapy. 2014;6 : 70. doi: 10.1186/s13195-014-0070-5 25478031

44. Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, et al. Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat Genet. 2012;44 : 511–516. doi: 10.1038/ng.2231 22446963

45. Chen W-C, Wang W-C, Okada Y, Chang W-P, Chou Y-H, Chang H-H, et al. rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis. Oncotarget. 2017;8 : 64180–64190. doi: 10.18632/oncotarget.19419 28969061

46. Akizuki S, Ishigaki K, Kochi Y, Law S-M, Matsuo K, Ohmura K, et al. PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes. Ann Rheum Dis. 2019;78 : 509–518. doi: 10.1136/annrheumdis-2018-214116 30679154

47. Henage LG, Exton JH, Brown HA. Kinetic analysis of a mammalian phospholipase D: allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides. J Biol Chem. 2006;281 : 3408–3417. doi: 10.1074/jbc.M508800200 16339153

48. Zhang GF, Patton WA, Lee FJ, Han JS, Rhee SG, Moss J, Vaughan M. Different ARF domains are required for the activation of cholera toxin and phospholipase D. J Biol Chem 1995;270(1):21–24. doi: 10.1074/jbc.270.1.21 7814376

49. Whyte L, Hassiotis S, Hattersley KJ, Hemsley KM, Hopwood JJ, Lau AA, Sargeant TJ. Lysosomal dysregulation in the murine AppNL-G-F/NL-G-F model of Alzheimer’s disease. Neuroscience 2020;429 : 143–155. doi: 10.1016/j.neuroscience.2019.12.042 31917339

50. Schommer J, Schrag M, Nackenoff A, Marwarha G, Ghribi O. Method for organotypic tissue culture in the aged animal. MethodsX. 2017;4 : 166–171. doi: 10.1016/j.mex.2017.03.003 28462173

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