Acta Neuropathologica

, Volume 132, Issue 1, pp 59–75 | Cite as

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

  • Benjamin Ettle
  • Bilal E. Kerman
  • Elvira Valera
  • Clarissa Gillmann
  • Johannes C. M. Schlachetzki
  • Simone Reiprich
  • Christian Büttner
  • Arif B. Ekici
  • André Reis
  • Michael Wegner
  • Tobias Bäuerle
  • Markus J. Riemenschneider
  • Eliezer Masliah
  • Fred H. Gage
  • Jürgen WinklerEmail author
Original Paper


Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.


Multiple system atrophy Oligodendrocytes Oligodendrocyte progenitor cells Myelin α-Synuclein 



This work was supported by the Interdisciplinary Center for Clinical Research (IZKF Erlangen, TP E18), the Bavarian State Ministry of Education and Culture, Science and Arts in the framework of the Bavarian Research Network Induced Pluripotent Stem Cells (ForIPS), the Deutsche Forschungsgemeinschaft (DFG grant INST 410/45-1 FUGG), and the NIH (AG5131, AG18440, NS092803). The study was supported in part by the G. Harold and Leila Y. Mathers Charitable Foundation, the JPB Foundation, the Leona M. and Harry B. Helmsley Charitable Trust. BE is an IZKF PhD student and was supported by the IZKF Erlangen to conduct experiments involving stem cells in the Laboratory of Genetics at the Salk Institute for Biological Studies, La Jolla, CA, USA. JCMS is supported by a research grant of the Deutsche Forschungsgemeinschaft (DFG grant no. SCHL 21021-1). The authors greatly acknowledge the NBB for providing human post-mortem tissue. Excellent technical assistance was provided by Holger Meixner, Someya Salem, Arianna Mei, Jazmin Florio, Maria Hirblinger, Petra Rothe, Angelika Diem, and Heike Friebel-Stange. We thank Beate Winner and Chichung Lie for scientific discussion and comments on the manuscript. Mary Lynn Gage is greatly acknowledged for editorial comments.

Compliance with ethical standards

Human brain samples used in this study were obtained from the NBB and have been collected from donors for or from whom a written informed consent for a brain autopsy and the use of the material and clinical information for research purposes had been obtained by the NBB. All animal procedures were conducted with approval of the animal care and use committees of the University of California San Diego, the Friedrich-Alexander-Universität Erlangen-Nürnberg, and the state of Bavaria.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

401_2016_1572_MOESM1_ESM.pdf (714 kb)
Supplementary material 1 (PDF 714 kb)


  1. 1.
    Ahmed Z, Asi YT, Sailer A, Lees AJ, Houlden H, Revesz T, Holton JL (2012) The neuropathology, pathophysiology and genetics of multiple system atrophy. Neuropathol Appl Neurobiol 38:4–24. doi: 10.1111/j.1365-2990.2011.01234.x CrossRefPubMedGoogle Scholar
  2. 2.
    Ahmed Z, Asi YT, Lees AJ, Revesz T, Holton JL (2013) Identification and quantification of oligodendrocyte precursor cells in multiple system atrophy, progressive supranuclear palsy and Parkinson’s disease. Brain Pathol 23:263–273. doi: 10.1111/j.1750-3639.2012.00637.x CrossRefPubMedGoogle Scholar
  3. 3.
    Anders S, Pyl PT, Huber W (2015) HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics 31:166–169. doi: 10.1093/bioinformatics/btu638 CrossRefPubMedGoogle Scholar
  4. 4.
    Asi YT, Simpson JE, Heath PR, Wharton SB, Lees AJ, Revesz T, Houlden H, Holton JL (2014) Alpha-synuclein mRNA expression in oligodendrocytes in MSA. Glia 62:964–970. doi: 10.1002/glia.22653 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bleasel JM, Hsiao JH, Halliday GM, Kim WS (2013) Increased expression of ABCA8 in multiple system atrophy brain is associated with changes in pathogenic proteins. J Parkinsons Dis 3:331–339. doi: 10.3233/JPD-130203 PubMedGoogle Scholar
  6. 6.
    Bottenstein JE, Sato GH (1979) Growth of a rat neuroblastoma cell line in serum-free supplemented medium. Proc Natl Acad Sci 76:514–517. doi: 10.1073/pnas.76.1.514 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T et al (2013) A regenerative approach to the treatment of multiple sclerosis. Nature 502:327–332. doi: 10.1038/nature12647 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Djelloul M, Holmqvist S, Boza-Serrano A, Azevedo C, Yeung MS, Goldwurm S, Frisen J, Deierborg T, Roybon L (2015) Alpha-synuclein expression in the oligodendrocyte lineage: an in vitro and in vivo study using rodent and human models. Stem Cell Rep 5:174–184. doi: 10.1016/j.stemcr.2015.07.002 CrossRefGoogle Scholar
  9. 9.
    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. doi: 10.1093/bioinformatics/bts635 CrossRefPubMedGoogle Scholar
  10. 10.
    Dodel R, Spottke A, Gerhard A, Reuss A, Reinecker S, Schimke N, Trenkwalder C, Sixel-Doring F, Herting B, Kamm C et al (2010) Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord 25:97–107. doi: 10.1002/mds.22732 CrossRefPubMedGoogle Scholar
  11. 11.
    Don AS, Hsiao JH, Bleasel JM, Couttas TA, Halliday GM, Kim WS (2014) Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun 2:150. doi: 10.1186/s40478-014-0150-6 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z (2009) GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinform 10:48. doi: 10.1186/1471-2105-10-48 CrossRefGoogle Scholar
  13. 13.
    Eschlbock S, Krismer F, Wenning GK (2016) Interventional trials in atypical parkinsonism. Parkinsonism Relat Disord 22(Suppl 1):S82–S92. doi: 10.1016/j.parkreldis.2015.09.038 CrossRefPubMedGoogle Scholar
  14. 14.
    Ettle B, Reiprich S, Deusser J, Schlachetzki JC, Xiang W, Prots I, Masliah E, Winner B, Wegner M, Winkler J (2014) Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells. Mol Cell Neurosci 62:68–78. doi: 10.1016/j.mcn.2014.06.012 CrossRefPubMedGoogle Scholar
  15. 15.
    Ettle B, Schlachetzki JC, Winkler J (2015) Oligodendroglia and myelin in neurodegenerative diseases: more than just bystanders? Mol Neurobiol. doi: 10.1007/s12035-015-9205-3 PubMedGoogle Scholar
  16. 16.
    Fanciulli A, Wenning GK (2015) Multiple-system atrophy. N Engl J Med 372:1375–1376. doi: 10.1056/NEJMc1501657 PubMedGoogle Scholar
  17. 17.
    Gaspard N, Bouschet T, Herpoel A, Naeije G, van den Ameele J, Vanderhaeghen P (2009) Generation of cortical neurons from mouse embryonic stem cells. Nat Protoc 4:1454–1463. doi: 10.1038/nprot.2009.157 CrossRefPubMedGoogle Scholar
  18. 18.
    Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, Inema I, Miller SE, Bieri G, Zuchero JB et al (2014) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344:1252304. doi: 10.1126/science.1252304 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676. doi: 10.1212/01.wnl.0000324625.00404.15 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gow A, Friedrich VL Jr, Lazzarini RA (1992) Myelin basic protein gene contains separate enhancers for oligodendrocyte and Schwann cell expression. J Cell Biol 119:605–616. doi: 10.1083/jcb.119.3.605 CrossRefPubMedGoogle Scholar
  21. 21.
    Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N et al (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613. doi: 10.1126/science.280.5369.1610 CrossRefPubMedGoogle Scholar
  22. 22.
    Groves AK, Barnett SC, Franklin RJ, Crang AJ, Mayer M, Blakemore WF, Noble M (1993) Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362:453–455. doi: 10.1038/362453a0 CrossRefPubMedGoogle Scholar
  23. 23.
    Irvine KA, Blakemore WF (2008) Remyelination protects axons from demyelination-associated axon degeneration. Brain 131:1464–1477. doi: 10.1093/brain/awn080 CrossRefPubMedGoogle Scholar
  24. 24.
    Kahle PJ, Neumann M, Ozmen L, Haass C (2000) Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson’s disease-associated protein. Ann N Y Acad Sci 920:33–41. doi: 10.1111/j.1749-6632-2000.tb06902.x CrossRefPubMedGoogle Scholar
  25. 25.
    Kerman BE, Kim HJ, Padmanabhan K, Mei A, Georges S, Joens MS, Fitzpatrick JA, Jappelli R, Chandross KJ, August P et al (2015) In vitro myelin formation using embryonic stem cells. Development 142:2213–2225. doi: 10.1242/dev.116517 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kuzdas-Wood D, Stefanova N, Jellinger KA, Seppi K, Schlossmacher MG, Poewe W, Wenning GK (2014) Towards translational therapies for multiple system atrophy. Prog Neurobiol 118:19–35. doi: 10.1016/j.pneurobio.2014.02.007 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lee J, Shmueli K, Kang BT, Yao B, Fukunaga M, van Gelderen P, Palumbo S, Bosetti F, Silva AC, Duyn JH (2012) The contribution of myelin to magnetic susceptibility-weighted contrasts in high-field MRI of the brain. Neuroimage 59:3967–3975. doi: 10.1016/j.neuroimage.2011.10.076 CrossRefPubMedGoogle Scholar
  28. 28.
    Lee PH, Lee JE, Kim HS, Song SK, Lee HS, Nam HS, Cheong JW, Jeong Y, Park HJ, Kim DJ et al (2012) A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann Neurol 72:32–40. doi: 10.1002/ana.23612 CrossRefPubMedGoogle Scholar
  29. 29.
    Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang PW et al (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487:443–448. doi: 10.1038/nature11314 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. doi: 10.1186/s13059-014-0550-8 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Low PA, Robertson D, Gilman S, Kaufmann H, Singer W, Biaggioni I, Freeman R, Perlman S, Hauser RA, Cheshire W et al (2014) Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 13:268–275. doi: 10.1016/S1474-4422(13)70301-6 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Low PA, Reich SG, Jankovic J, Shults CW, Stern MB, Novak P, Tanner CM, Gilman S, Marshall FJ, Wooten F et al (2015) Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol 14:710–719. doi: 10.1016/S1474-4422(15)00058-7 CrossRefPubMedGoogle Scholar
  33. 33.
    Mandler M, Valera E, Rockenstein E, Mante M, Weninger H, Patrick C, Adame A, Schmidhuber S, Santic R, Schneeberger A et al (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10:10. doi: 10.1186/s13024-015-0008-9 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–657. doi: 10.1016/j.stem.2008.10.001 CrossRefPubMedGoogle Scholar
  35. 35.
    Matsuo A, Akiguchi I, Lee GC, McGeer EG, McGeer PL, Kimura J (1998) Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol 153:735–744. doi: 10.1016/S0002-9440(10)65617-9 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    May VE, Ettle B, Poehler AM, Nuber S, Ubhi K, Rockenstein E, Winner B, Wegner M, Masliah E, Winkler J (2014) alpha-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiol Aging 35:2357–2368. doi: 10.1016/j.neurobiolaging.2014.02.028 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, Richardson WD (2014) Motor skill learning requires active central myelination. Science 346:318–322. doi: 10.1126/science.1254960 CrossRefPubMedGoogle Scholar
  38. 38.
    Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100. doi: 10.1016/0022-510X(89)90219-0 CrossRefPubMedGoogle Scholar
  39. 39.
    Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Bruck W, Lucchinetti C, Lassmann H (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165–3172. doi: 10.1093/brain/awl217 CrossRefPubMedGoogle Scholar
  40. 40.
    Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM (2000) alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62:9–14. doi: 10.1002/1097-4547(20001001)62:1<9:AID-JNR2>3.0.CO;2-U CrossRefPubMedGoogle Scholar
  41. 41.
    Salvesen L, Ullerup BH, Sunay FB, Brudek T, Lokkegaard A, Agander TK, Winge K, Pakkenberg B (2015) Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy—A stereological study. Neurobiol Dis 74:104–113. doi: 10.1016/j.nbd.2014.11.008 CrossRefPubMedGoogle Scholar
  42. 42.
    Scholz J, Klein MC, Behrens TE, Johansen-Berg H (2009) Training induces changes in white-matter architecture. Nat Neurosci 12:1370–1371. doi: 10.1038/nn.2412 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R, Gibbs JR, Simon-Sanchez J et al (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65:610–614. doi: 10.1002/ana.21685 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Seppi K, Peralta C, Diem-Zangerl A, Puschban Z, Mueller J, Poewe W, Wenning GK (2006) Placebo-controlled trial of riluzole in multiple system atrophy. Eur J Neurol 13:1146–1148. doi: 10.1111/j.1468-1331.2006.01452.x CrossRefPubMedGoogle Scholar
  45. 45.
    Shults CW, Rockenstein E, Crews L, Adame A, Mante M, Larrea G, Hashimoto M, Song D, Iwatsubo T, Tsuboi K et al (2005) Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci 25:10689–10699. doi: 10.1523/JNEUROSCI.3527-05.2005 CrossRefPubMedGoogle Scholar
  46. 46.
    Simons M, Nave KA (2015) Oligodendrocytes: myelination and axonal support. Cold Spring Harb Perspect Biol. doi: 10.1101/cshperspect.a020479 PubMedGoogle Scholar
  47. 47.
    Song YJ, Lundvig DM, Huang Y, Gai WP, Blumbergs PC, Hojrup P, Otzen D, Halliday GM, Jensen PH (2007) p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171:1291–1303. doi: 10.2353/ajpath.2007.070201 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Stefanova N, Kaufmann WA, Humpel C, Poewe W, Wenning GK (2012) Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. Acta Neuropathol 124:51–65. doi: 10.1007/s00401-012-0977-5 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Uyama N, Uchihara T, Mochizuki Y, Nakamura A, Takahashi R, Mizutani T (2009) Selective nuclear shrinkage of oligodendrocytes lacking glial cytoplasmic inclusions in multiple system atrophy: a 3-dimensional volumetric study. J Neuropathol Exp Neurol 68:1084–1091. doi: 10.1097/NEN.0b013e3181b67678 CrossRefPubMedGoogle Scholar
  50. 50.
    Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246. doi: 10.1002/ana.21465 CrossRefPubMedGoogle Scholar
  51. 51.
    Wilkins A, Kondo Y, Song J, Liu S, Compston A, Black JA, Waxman SG, Duncan ID (2010) Slowly progressive axonal degeneration in a rat model of chronic, nonimmune-mediated demyelination. J Neuropathol Exp Neurol 69:1256–1269. doi: 10.1097/NEN.0b013e3181ffc317 CrossRefPubMedGoogle Scholar
  52. 52.
    Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, Trojanowski JQ, Lee VM (2005) Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45:847–859. doi: 10.1016/j.neuron.2005.01.032 CrossRefPubMedGoogle Scholar
  53. 53.
    Yeung MS, Zdunek S, Bergmann O, Bernard S, Salehpour M, Alkass K, Perl S, Tisdale J, Possnert G, Brundin L et al (2014) Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 159:766–774. doi: 10.1016/j.cell.2014.10.011 CrossRefPubMedGoogle Scholar
  54. 54.
    Young KM, Psachoulia K, Tripathi RB, Dunn SJ, Cossell L, Attwell D, Tohyama K, Richardson WD (2013) Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron 77:873–885. doi: 10.1016/j.neuron.2013.01.006 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Benjamin Ettle
    • 1
  • Bilal E. Kerman
    • 2
    • 8
  • Elvira Valera
    • 3
  • Clarissa Gillmann
    • 4
  • Johannes C. M. Schlachetzki
    • 1
    • 9
  • Simone Reiprich
    • 5
  • Christian Büttner
    • 6
  • Arif B. Ekici
    • 6
  • André Reis
    • 6
  • Michael Wegner
    • 5
  • Tobias Bäuerle
    • 4
  • Markus J. Riemenschneider
    • 7
  • Eliezer Masliah
    • 3
  • Fred H. Gage
    • 2
  • Jürgen Winkler
    • 1
    Email author
  1. 1.Department of Molecular NeurologyUniversity Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  2. 2.Laboratory of GeneticsThe Salk Institute for Biological StudiesLa JollaUSA
  3. 3.Department of NeurosciencesUniversity of California San DiegoLa JollaUSA
  4. 4.Institute of RadiologyUniversity Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  5. 5.Institute of BiochemistryFriedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  6. 6.Institute of Human GeneticsUniversity Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  7. 7.Department of NeuropathologyRegensburg University HospitalRegensburgGermany
  8. 8.Research Center for Regenerative and Restorative MedicineIstanbul Medipol UniversityIstanbulTurkey
  9. 9.Department of Cellular and Molecular MedicineUniversity of California San DiegoLa JollaUSA

Personalised recommendations