Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles
Autoři:
Kathryn A. Jewett aff001; Ruth E. Thomas aff001; Chi Q. Phan aff001; Bernice Lin aff003; Gillian Milstein aff001; Selina Yu aff001; Lisa F. Bettcher aff004; Fausto Carnevale Neto aff004; Danijel Djukovic aff004; Daniel Raftery aff004; Leo J. Pallanck aff001; Marie Y. Davis aff003
Působiště autorů:
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
aff001; Department of Biology, Juniata College, Huntingdon, Pennsylvania, United States of America
aff002; VA Puget Sound Healthcare System, Seattle, Washington, United States of America
aff003; Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington, United States of America
aff004; Department of Neurology, University of Washington, Seattle, Washington, United States of America
aff005
Vyšlo v časopise:
Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles. PLoS Genet 17(2): e1008859. doi:10.1371/journal.pgen.1008859
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008859
Souhrn
Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson’s disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in glucosidase, beta acid 1 (GBA), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression. To explore how GBA mutations influence pathogenesis, we previously created a Drosophila model of GBA deficiency (Gba1b) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis of Gba1b mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from Gba1b mutants. Accordingly, we hypothesized that GBA may influence pathogenic protein aggregate spread via EVs. We found that accumulation of ubiquitinated proteins and Ref(2)P, Drosophila homologue of mammalian p62, were reduced in muscle and brain tissue of Gba1b flies by ectopic expression of wildtype GCase in muscle. Neuronal GCase expression also rescued protein aggregation both cell-autonomously in brain and non-cell-autonomously in muscle. Muscle-specific GBA expression reduced the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from Gba1b flies. Perturbing EV biogenesis through neutral sphingomyelinase (nSMase), an enzyme important for EV release and ceramide metabolism, enhanced protein aggregation when knocked down in muscle, but did not modify Gba1b mutant protein aggregation when knocked down in neurons. Lipidomic analysis of nSMase knockdown on ceramide and glucosylceramide levels suggested that Gba1b mutant protein aggregation may depend on relative depletion of specific ceramide species often enriched in EVs. Finally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency promotes accelerated protein aggregate spread between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread.
Klíčová slova:
Actins – Biosynthesis – Drosophila melanogaster – Muscle proteins – Muscle tissue – Parkinson disease – Protein aggregation – principal component analysis
Zdroje
1. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. European journal of epidemiology. 2011;26 Suppl 1:S1–58. Epub 2011/06/03. doi: 10.1007/s10654-011-9581-6 21626386.
2. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet. 2004;363(9423):1783–93. doi: 10.1016/S0140-6736(04)16305-8 15172778.
3. Parkinson J. An essay on the shaking palsy. 1817. The Journal of neuropsychiatry and clinical neurosciences. 2002;14(2):223–36; discussion 2. doi: 10.1176/jnp.14.2.223 11983801.
4. Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson’s disease. Parkinsonism & related disorders. 2007;13(6):323–32. doi: 10.1016/j.parkreldis.2006.12.014 17349813.
5. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211. doi: 10.1016/s0197-4580(02)00065-9 12498954.
6. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338(6109):949–53. Epub 2012/11/20. doi: 10.1126/science.1227157 23161999; PubMed Central PMCID: PMC3552321.
7. Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ, et al. Widespread transneuronal propagation of alpha-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med. 2016;213(9):1759–78. Epub 2016/08/10. doi: 10.1084/jem.20160368 27503075; PubMed Central PMCID: PMC4995088.
8. Chu Y, Muller S, Tavares A, Barret O, Alagille D, Seibyl J, et al. Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes. Brain. 2019;142(11):3565–79. Epub 2019/10/04. doi: 10.1093/brain/awz296 31580415.
9. Sidransky E, Samaddar T, Tayebi N. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology. 2009;73(17):1424–5, author reply 5–6. Epub 2009/10/28. doi: 10.1212/WNL.0b013e3181b28601 19858467.
10. Pankratz N, Beecham GW, DeStefano AL, Dawson TM, Doheny KF, Factor SA, et al. Meta-analysis of Parkinson’s disease: identification of a novel locus, RIT2. Ann Neurol. 2012;71(3):370–84. Epub 2012/03/28. doi: 10.1002/ana.22687 22451204; PubMed Central PMCID: PMC3354734.
11. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, et al. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology. 2012;79(19):1944–50. Epub 2012/10/05. doi: 10.1212/WNL.0b013e3182735e9a 23035075; PubMed Central PMCID: PMC3484986.
12. Tayebi N, Callahan M, Madike V, Stubblefield BK, Orvisky E, Krasnewich D, et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Molecular genetics and metabolism. 2001;73(4):313–21. doi: 10.1006/mgme.2001.3201 11509013.
13. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361(17):1651–61. doi: 10.1056/NEJMoa0901281 19846850; PubMed Central PMCID: PMC2856322.
14. Clark LN, Kartsaklis LA, Wolf Gilbert R, Dorado B, Ross BM, Kisselev S, et al. Association of glucocerebrosidase mutations with dementia with lewy bodies. Arch Neurol. 2009;66(5):578–83. Epub 2009/05/13. doi: 10.1001/archneurol.2009.54 19433657; PubMed Central PMCID: PMC2758782.
15. Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008;70(24):2277–83. doi: 10.1212/01.wnl.0000304039.11891.29 18434642.
16. Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, et al. GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2015;30(3):407–11. Epub 2014/12/03. doi: 10.1002/mds.26071 25448271.
17. Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. Neurobiol Aging. 2016;37:209 e1- e7. Epub 2015/11/26. doi: 10.1016/j.neurobiolaging.2015.09.014 26601739; PubMed Central PMCID: PMC4688052.
18. Davis MY, Johnson CO, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, et al. Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol. 2016;73(10):1217–1224. Epub 2016/08/30. doi: 10.1001/jamaneurol.2016.2245 27571329; PubMed Central PMCID: PMC5056861.
19. Davis MY, Trinh K, Thomas RE, Yu S, Germanos AA, Whitley BN, et al. Glucocerebrosidase Deficiency in Drosophila Results in alpha-Synuclein-Independent Protein Aggregation and Neurodegeneration. PLoS Genet. 2016;12(3):e1005944. Epub 2016/03/29. doi: 10.1371/journal.pgen.1005944 27019408; PubMed Central PMCID: PMC4809718.
20. Kinghorn KJ, Gronke S, Castillo-Quan JI, Woodling NS, Li L, Sirka E, et al. A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin. J Neurosci. 2016;36(46):11654–70. Epub 2016/11/18. doi: 10.1523/JNEUROSCI.4527-15.2016 27852774; PubMed Central PMCID: PMC5125225.
21. Kawasaki H, Suzuki T, Ito K, Takahara T, Goto-Inoue N, Setou M, et al. Minos-insertion mutant of the Drosophila GBA gene homologue showed abnormal phenotypes of climbing ability, sleep and life span with accumulation of hydroxy-glucocerebroside. Gene. 2017;614:49–55. Epub 2017/03/14. doi: 10.1016/j.gene.2017.03.004 28286087.
22. Maor G, Cabasso O, Krivoruk O, Rodriguez J, Steller H, Segal D, et al. The contribution of mutant GBA to the development of Parkinson disease in Drosophila. Hum Mol Genet. 2016;25(13):2712–27. Epub 2016/05/11. doi: 10.1093/hmg/ddw129 27162249; PubMed Central PMCID: PMC6390410.
23. Thomas RE, Vincow ES, Merrihew GE, MacCoss MJ, Davis MY, Pallanck LJ. Glucocerebrosidase deficiency promotes protein aggregation through dysregulation of extracellular vesicles. PLoS Genet. 2018;14(9):e1007694. Epub 2018/09/27. doi: 10.1371/journal.pgen.1007694 30256786; PubMed Central PMCID: PMC6175534.
24. Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89. Epub 2014/10/08. doi: 10.1146/annurev-cellbio-101512-122326 25288114.
25. van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19(4):213–28. Epub 2018/01/18. doi: 10.1038/nrm.2017.125 29339798.
26. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83. Epub 2013/02/20. doi: 10.1083/jcb.201211138 23420871; PubMed Central PMCID: PMC3575529.
27. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75(2):193–208. Epub 2017/07/25. doi: 10.1007/s00018-017-2595-9 28733901; PubMed Central PMCID: PMC5756260.
28. Stuendl A, Kunadt M, Kruse N, Bartels C, Moebius W, Danzer KM, et al. Induction of alpha-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies. Brain. 2016;139(Pt 2):481–94. Epub 2015/12/10. doi: 10.1093/brain/awv346 26647156; PubMed Central PMCID: PMC4805087.
29. Xiao T, Zhang W, Jiao B, Pan CZ, Liu X, Shen L. The role of exosomes in the pathogenesis of Alzheimer’ disease. Transl Neurodegener. 2017;6:3. Epub 2017/02/12. doi: 10.1186/s40035-017-0072-x 28184302; PubMed Central PMCID: PMC5289036.
30. Jia L, Qiu Q, Zhang H, Chu L, Du Y, Zhang J, et al. Concordance between the assessment of Abeta42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement. 2019;15(8):1071–80. Epub 2019/08/20. doi: 10.1016/j.jalz.2019.05.002 31422798.
31. Basso M, Pozzi S, Tortarolo M, Fiordaliso F, Bisighini C, Pasetto L, et al. Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J Biol Chem. 2013;288(22):15699–711. Epub 2013/04/18. doi: 10.1074/jbc.M112.425066 23592792; PubMed Central PMCID: PMC3668729.
32. Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, et al. Cells release prions in association with exosomes. Proc Natl Acad Sci U S A. 2004;101(26):9683–8. Epub 2004/06/24. doi: 10.1073/pnas.0308413101 15210972; PubMed Central PMCID: PMC470735.
33. Robertson C, Booth SA, Beniac DR, Coulthart MB, Booth TF, McNicol A. Cellular prion protein is released on exosomes from activated platelets. Blood. 2006;107(10):3907–11. Epub 2006/01/26. doi: 10.1182/blood-2005-02-0802 16434486.
34. Minakaki G, Menges S, Kittel A, Emmanouilidou E, Schaeffner I, Barkovits K, et al. Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy. 2018;14(1):98–119. Epub 2017/12/05. doi: 10.1080/15548627.2017.1395992 29198173; PubMed Central PMCID: PMC5846507.
35. Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012;7:42. doi: 10.1186/1750-1326-7-42 22920859; PubMed Central PMCID: PMC3483256.
36. Nongthomba U, Pasalodos-Sanchez S, Clark S, Clayton JD, Sparrow JC. Expression and function of the Drosophila ACT88F actin isoform is not restricted to the indirect flight muscles. J Muscle Res Cell Motil. 2001;22(2):111–9. Epub 2001/08/25. doi: 10.1023/a:1010308326890 11519734.
37. Nezis IP, Simonsen A, Sagona AP, Finley K, Gaumer S, Contamine D, et al. Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J Cell Biol. 2008;180(6):1065–71. Epub 2008/03/19. doi: 10.1083/jcb.200711108 18347073; PubMed Central PMCID: PMC2290837.
38. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244–7. Epub 2008/03/01. doi: 10.1126/science.1153124 18309083.
39. Guo BB, Bellingham SA, Hill AF. The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. J Biol Chem. 2015;290(6):3455–67. Epub 2014/12/17. doi: 10.1074/jbc.M114.605253 25505180; PubMed Central PMCID: PMC4319014.
40. Shamseddine AA, Airola MV, Hannun YA. Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes. Adv Biol Regul. 2015;57:24–41. Epub 2014/12/04. doi: 10.1016/j.jbior.2014.10.002 25465297; PubMed Central PMCID: PMC4684640.
41. Skotland T, Sandvig K, Llorente A. Lipids in exosomes: Current knowledge and the way forward. Prog Lipid Res. 2017;66:30–41. Epub 2017/03/28. doi: 10.1016/j.plipres.2017.03.001 28342835.
42. Sandhof CA, Hoppe SO, Druffel-Augustin S, Gallrein C, Kirstein J, Voisine C, et al. Reducing INS-IGF1 signaling protects against non-cell autonomous vesicle rupture caused by SNCA spreading. Autophagy. 2019:1–22. Epub 2019/07/30. doi: 10.1080/15548627.2019.1643657 31354022.
43. Demontis F, Perrimon N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell. 2010;143(5):813–25. Epub 2010/11/30. doi: 10.1016/j.cell.2010.10.007 21111239; PubMed Central PMCID: PMC3066043.
44. Mathews PM, Levy E. Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases. Front Neurosci. 2019;13:1347. Epub 2020/01/09. doi: 10.3389/fnins.2019.01347 31911768; PubMed Central PMCID: PMC6920185.
45. Fussi N, Hollerhage M, Chakroun T, Nykanen NP, Rosler TW, Koeglsperger T, et al. Exosomal secretion of alpha-synuclein as protective mechanism after upstream blockage of macroautophagy. Cell Death Dis. 2018;9(7):757. Epub 2018/07/11. doi: 10.1038/s41419-018-0816-2 29988147; PubMed Central PMCID: PMC6037700.
46. Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14(10):1036–45. Epub 2012/09/18. doi: 10.1038/ncb2574 22983114.
47. Romero-Calvo I, Ocon B, Martinez-Moya P, Suarez MD, Zarzuelo A, Martinez-Augustin O, et al. Reversible Ponceau staining as a loading control alternative to actin in Western blots. Anal Biochem. 2010;401(2):318–20. Epub 2010/03/09. doi: 10.1016/j.ab.2010.02.036 20206115.
48. Thacker JS, Yeung DH, Staines WR, Mielke JG. Total protein or high-abundance protein: Which offers the best loading control for Western blotting? Anal Biochem. 2016;496:76–8. Epub 2015/12/27. doi: 10.1016/j.ab.2015.11.022 26706797.
49. Xia J, Wishart DS. Using MetaboAnalyst 3.0 for Comprehensive Metabolomics Data Analysis. Curr Protoc Bioinformatics. 2016;55:14 0 1–0 91. Epub 2016/09/08. doi: 10.1002/cpbi.11 27603023.
Článek vyšel v časopise
PLOS Genetics
2021 Číslo 2
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles
- ATF3 downmodulates its new targets IFI6 and IFI27 to suppress the growth and migration of tongue squamous cell carcinoma cells
- Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder
- Four families of folate-independent methionine synthases
