Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?

Molecular Neurobiology

Volumn 53, Issue 5, 2016, Pages 3046-3062

  Ettle, Benjamin ^a   Schlachetzki, Johannes C M ^a   Winkler, Jürgen ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

Author keywords

Alpha synuclein; Multiple system atrophy; Myelin; Neurodegenerative diseases; Oligodendrocyte progenitor cells; Oligodendrocytes

Indexed keywords

ABC TRANSPORTER A8; ALPHA SYNUCLEIN; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; MYELIN;

AMYLOID PLAQUE; AMYOTROPHIC LATERAL SCLEROSIS; ASTROCYTOSIS; CELL SURVIVAL; DEGENERATIVE DISEASE; DEMYELINATION; DISEASE ASSOCIATION; DISEASE COURSE; GLIA CELL; GLIOSIS; HUMAN; MOLECULAR PATHOLOGY; MULTIPLE SCLEROSIS; NERVE CELL NETWORK; NERVE CELL PLASTICITY; NEUROPATHOLOGY; NONHUMAN; OLIGODENDROGLIA; PROTEIN EXPRESSION; REVIEW; SHY DRAGER SYNDROME; ANIMAL; EVOLUTION; MYELIN SHEATH; PATHOLOGY;

ANIMALS; BIOLOGICAL EVOLUTION; HUMANS; MYELIN SHEATH; NEURODEGENERATIVE DISEASES; OLIGODENDROGLIA;

EID: 84929428909     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-015-9205-3     Document Type: Review

References (213)

1. Prots I, Veber V, Brey S, Campioni S, Buder K, Riek R, Bohm KJ, Winner B (2013) alpha-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J Biol Chem 288(30):21742–21754. doi:10.1074/jbc.M113.451815
2. Millecamps S, Julien JP (2013) Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci 14(3):161–176. doi:10.1038/nrn3380
3. Itoh K, Nakamura K, Iijima M, Sesaki H (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23(2):64–71. doi:10.1016/j.tcb.2012.10.006
4. Klucken J, Poehler AM, Ebrahimi-Fakhari D, Schneider J, Nuber S, Rockenstein E, Schlotzer-Schrehardt U, Hyman BT et al (2012) Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway. Autophagy 8(5):754–766. doi:10.4161/auto.19371
5. Dantuma NP, Bott LC (2014) The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution. Front Mol Neurosci 7:70. doi:10.3389/fnmol.2014.00070
6. Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14(7):463–477. doi:10.1038/nri3705
7. Menichella DM, Majdan M, Awatramani R, Goodenough DA, Sirkowski E, Scherer SS, Paul DL (2006) Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. J Neurosci Off J Soc Neurosci 26(43):10984–10991. doi:10.1523/JNEUROSCI.0304-06.2006
8. Iwata NK, Aoki S, Okabe S, Arai N, Terao Y, Kwak S, Abe O, Kanazawa I et al (2008) Evaluation of corticospinal tracts in ALS with diffusion tensor MRI and brainstem stimulation. Neurology 70(7):528–532. doi:10.1212/01.wnl.0000299186.72374.19
9. Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR (2009) Oligodendrocytes and myelination: the role of iron. Glia 57(5):467–478. doi:10.1002/glia.20784
10. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13(10):1045–1060. doi:10.1016/S1474-4422(14)70117-6
11. Bartzokis G, Tishler TA, Shin IS, Lu PH, Cummings JL (2004) Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Ann N Y Acad Sci 1012:224–236
12. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485(7399):517–521. doi:10.1038/nature11007
13. Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Mobius W et al (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11(7):e1001604. doi:10.1371/journal.pbio.1001604
14. Crawford AH, Stockley JH, Tripathi RB, Richardson WD, Franklin RJ (2014) Oligodendrocyte progenitors: adult stem cells of the central nervous system? Exp Neurol 260:50–55. doi:10.1016/j.expneurol.2014.04.027
15. Nishiyama A, Komitova M, Suzuki R, Zhu X (2009) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci 10(1):9–22. doi:10.1038/nrn2495
16. Pelvig DP, Pakkenberg H, Stark AK, Pakkenberg B (2008) Neocortical glial cell numbers in human brains. Neurobiol Aging 29(11):1754–1762. doi:10.1016/j.neurobiolaging.2007.04.013
17. Beirowski B (2013) Concepts for regulation of axon integrity by enwrapping glia. Front Cell Neurosci 7:256. doi:10.3389/fncel.2013.00256
18. Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A et al (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487(7408):443–448. doi:10.1038/nature11314
19. Wilkins A, Majed H, Layfield R, Compston A, Chandran S (2003) Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J Neurosci Off J Soc Neurosci 23(12):4967–4974
20. Du Y, Dreyfus CF (2002) Oligodendrocytes as providers of growth factors. J Neurosci Res 68(6):647–654. doi:10.1002/jnr.10245
21. Dai X, Lercher LD, Clinton PM, Du Y, Livingston DL, Vieira C, Yang L, Shen MM et al (2003) The trophic role of oligodendrocytes in the basal forebrain. J Neurosci Off J Soc Neurosci 23(13):5846–5853
22. Richardson WD, Kessaris N, Pringle N (2006) Oligodendrocyte wars. Nat Rev Neurosci 7(1):11–18. doi:10.1038/nrn1826
23. Calza L, Fernandez M, Giuliani A, Aloe L, Giardino L (2002) Thyroid hormone activates oligodendrocyte precursors and increases a myelin-forming protein and NGF content in the spinal cord during experimental allergic encephalomyelitis. Proc Natl Acad Sci U S A 99(5):3258–3263. doi:10.1073/pnas.052704499
24. McTigue DM, Horner PJ, Stokes BT, Gage FH (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci Off J Soc Neurosci 18(14):5354–5365
25. Valerio A, Ferrario M, Dreano M, Garotta G, Spano P, Pizzi M (2002) Soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro differentiation of purified rat oligodendroglial lineage cells. Mol Cell Neurosci 21(4):602–615
26. Larsen PH, DaSilva AG, Conant K, Yong VW (2006) Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and -12 null mice. J Neurosci Off J Soc Neurosci 26(8):2207–2214. doi:10.1523/JNEUROSCI.1880-05.2006
27. Noble M, Murray K, Stroobant P, Waterfield MD, Riddle P (1988) Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature 333(6173):560–562. doi:10.1038/333560a0
28. Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci Off J Soc Neurosci 26(1):328–332. doi:10.1523/JNEUROSCI.2615-05.2006
29. Stolt CC, Rehberg S, Ader M, Lommes P, Riethmacher D, Schachner M, Bartsch U, Wegner M (2002) Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10. Genes Dev 16(2):165–170. doi:10.1101/gad.215802
30. Meijer DH, Kane MF, Mehta S, Liu H, Harrington E, Taylor CM, Stiles CD, Rowitch DH (2012) Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2. Nat Rev Neurosci 13(12):819–831. doi:10.1038/nrn3386
31. Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, Sanai N, Franklin RJ et al (2009) Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev 23(13):1571–1585. doi:10.1101/gad.1806309
32. Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, Weinmaster G, Barres BA (1998) Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21(1):63–75
33. Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, Ibrahim A, Ligon KL et al (2009) Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 138(1):172–185. doi:10.1016/j.cell.2009.04.031
34. Nishiyama A, Watanabe M, Yang Z, Bu J (2002) Identity, distribution, and development of polydendrocytes: NG2-expressing glial cells. J Neurocytol 31(6–7):437–455
35. Dawson MR, Polito A, Levine JM, Reynolds R (2003) NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol Cell Neurosci 24(2):476–488
36. Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9(11):839–855. doi:10.1038/nrn2480
37. Smith KJ, Blakemore WF, McDonald WI (1979) Central remyelination restores secure conduction. Nature 280(5721):395–396
38. 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(6419):453–455. doi:10.1038/362453a0
39. Vigano F, Mobius W, Gotz M, Dimou L (2013) Transplantation reveals regional differences in oligodendrocyte differentiation in the adult brain. Nat Neurosci 16(10):1370–1372. doi:10.1038/nn.3503
40. 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(5):873–885. doi:10.1016/j.neuron.2013.01.006
41. Gibson EM, Purger D, Mount CW, Goldstein AK, Lin GL, Wood LS, Inema I, Miller SE et al (2014) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344(6183):1252304. doi:10.1126/science.1252304
42. 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(6207):318–322. doi:10.1126/science.1254960
43. Yeung MS, Zdunek S, Bergmann O, Bernard S, Salehpour M, Alkass K, Perl S, Tisdale J et al (2014) Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 159(4):766–774. doi:10.1016/j.cell.2014.10.011
44. Richardson WD, Young KM, Tripathi RB, McKenzie I (2011) NG2-glia as multipotent neural stem cells: fact or fantasy? Neuron 70(4):661–673. doi:10.1016/j.neuron.2011.05.013
45. Rivers LE, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N, Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat Neurosci 11(12):1392–1401. doi:10.1038/nn.2220
46. Robins SC, Trudel E, Rotondi O, Liu X, Djogo T, Kryzskaya D, Bourque CW, Kokoeva MV (2013) Evidence for NG2-glia derived, adult-born functional neurons in the hypothalamus. PLoS ONE 8(10):e78236. doi:10.1371/journal.pone.0078236
47. Guo F, Maeda Y, Ma J, Xu J, Horiuchi M, Miers L, Vaccarino F, Pleasure D (2010) Pyramidal neurons are generated from oligodendroglial progenitor cells in adult piriform cortex. J Neurosci Off J Soc Neurosci 30(36):12036–12049. doi:10.1523/JNEUROSCI.1360-10.2010
48. Clarke LE, Young KM, Hamilton NB, Li H, Richardson WD, Attwell D (2012) Properties and fate of oligodendrocyte progenitor cells in the corpus callosum, motor cortex, and piriform cortex of the mouse. J Neurosci Off J Soc Neurosci 32(24):8173–8185. doi:10.1523/JNEUROSCI.0928-12.2012
49. Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68(4):668–681. doi:10.1016/j.neuron.2010.09.009
50. Zhu X, Hill RA, Dietrich D, Komitova M, Suzuki R, Nishiyama A (2011) Age-dependent fate and lineage restriction of single NG2 cells. Development 138(4):745–753. doi:10.1242/dev.047951
51. Ju P, Zhang S, Yeap Y, Feng Z (2012) Induction of neuronal phenotypes from NG2+ glial progenitors by inhibiting epidermal growth factor receptor in mouse spinal cord injury. Glia 60(11):1801–1814. doi:10.1002/glia.22398
52. Heinrich C, Bergami M, Gascon S, Lepier A, Vigano F, Dimou L, Sutor B, Berninger B et al (2014) Sox2-mediated conversion of NG2 glia into induced neurons in the injured adult cerebral cortex. Stem Cell Rep. doi:10.1016/j.stemcr.2014.10.007
53. Sakry D, Neitz A, Singh J, Frischknecht R, Marongiu D, Biname F, Perera SS, Endres K et al (2014) Oligodendrocyte precursor cells modulate the neuronal network by activity-dependent ectodomain cleavage of glial NG2. PLoS Biol 12(11):e1001993. doi:10.1371/journal.pbio.1001993
54. Zalc B, Goujet D, Colman D (2008) The origin of the myelination program in vertebrates. Curr Biol CB 18(12):R511–512. doi:10.1016/j.cub.2008.04.010
55. Hartline DK, Colman DR (2007) Rapid conduction and the evolution of giant axons and myelinated fibers. Curr Biol CB 17(1):R29–35. doi:10.1016/j.cub.2006.11.042
56. Bartzokis G, Sultzer D, Lu PH, Nuechterlein KH, Mintz J, Cummings JL (2004) Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical “disconnection” in aging and Alzheimer’s disease. Neurobiol Aging 25(7):843–851. doi:10.1016/j.neurobiolaging.2003.09.005
57. Schoenemann PT, Sheehan MJ, Glotzer LD (2005) Prefrontal white matter volume is disproportionately larger in humans than in other primates. Nat Neurosci 8(2):242–252. doi:10.1038/nn1394
58. Smaers JB, Schleicher A, Zilles K, Vinicius L (2010) Frontal white matter volume is associated with brain enlargement and higher structural connectivity in anthropoid primates. PLoS ONE 5(2):e9123. doi:10.1371/journal.pone.0009123
59. Deoni SC, O’Muircheartaigh J, Elison JT, Walker L, Doernberg E, Waskiewicz N, Dirks H, Piryatinsky I et al (2014) White matter maturation profiles through early childhood predict general cognitive ability. Brain Struct Funct. doi:10.1007/s00429-014-0947-x
60. Hagmann P, Sporns O, Madan N, Cammoun L, Pienaar R, Wedeen VJ, Meuli R, Thiran JP et al (2010) White matter maturation reshapes structural connectivity in the late developing human brain. Proc Natl Acad Sci U S A 107(44):19067–19072. doi:10.1073/pnas.1009073107
61. Nagy Z, Westerberg H, Klingberg T (2004) Maturation of white matter is associated with the development of cognitive functions during childhood. J Cogn Neurosci 16(7):1227–1233. doi:10.1162/0898929041920441
62. Hasegawa M, Houdou S, Mito T, Takashima S, Asanuma K, Ohno T (1992) Development of myelination in the human fetal and infant cerebrum: a myelin basic protein immunohistochemical study. Brain Dev 14(1):1–6
63. Miller DJ, Duka T, Stimpson CD, Schapiro SJ, Baze WB, McArthur MJ, Fobbs AJ, Sousa AM et al (2012) Prolonged myelination in human neocortical evolution. Proc Natl Acad Sci U S A 109(41):16480–16485. doi:10.1073/pnas.1117943109
64. Sakai T, Mikami A, Tomonaga M, Matsui M, Suzuki J, Hamada Y, Tanaka M, Miyabe-Nishiwaki T et al (2011) Differential prefrontal white matter development in chimpanzees and humans. Curr Biol CB 21(16):1397–1402. doi:10.1016/j.cub.2011.07.019
65. Bartzokis G, Beckson M, Lu PH, Nuechterlein KH, Edwards N, Mintz J (2001) Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. Arch Gen Psychiatry 58(5):461–465
66. Bankston AN, Mandler MD, Feng Y (2013) Oligodendroglia and neurotrophic factors in neurodegeneration. Neurosci Bull 29(2):216–228. doi:10.1007/s12264-013-1321-3
67. De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain J Neurol 121(Pt 8):1469–1477
68. Fu L, Matthews PM, De Stefano N, Worsley KJ, Narayanan S, Francis GS, Antel JP, Wolfson C et al (1998) Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain J Neurol 121(Pt 1):103–113
69. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285. doi:10.1056/NEJM199801293380502
70. 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(12):1256–1269. doi:10.1097/NEN.0b013e3181ffc317
71. Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M et al (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157(1):267–276. doi:10.1016/S0002-9440(10)64537-3
72. Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F et al (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280(5369):1610–1613
73. Nave KA (2010) Myelination and support of axonal integrity by glia. Nature 468(7321):244–252. doi:10.1038/nature09614
74. Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J, Bruck W (2008) Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain J Neurol 131(Pt 7):1749–1758. doi:10.1093/brain/awn096
75. Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346(3):165–173. doi:10.1056/NEJMoa010994
76. Seven A, Aslan M, Incir S, Altintas A (2013) Evaluation of oxidative and nitrosative stress in relapsing remitting multiple sclerosis: effect of corticosteroid therapy. Folia Neuropathol Assoc Pol Neuropathol Med Res Cent Pol Acad Sci 51(1):58–64
77. Bizzozero OA, DeJesus G, Bixler HA, Pastuszyn A (2005) Evidence of nitrosative damage in the brain white matter of patients with multiple sclerosis. Neurochem Res 30(1):139–149
78. Kremer D, Schichel T, Forster M, Tzekova N, Bernard C, van der Valk P, van Horssen J, Hartung HP et al (2013) Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann Neurol 74(5):721–732. doi:10.1002/ana.23970
79. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10(Suppl):S2–9. doi:10.1038/nm1067
80. Bartzokis G (2004) Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging 25(1):5–18, author reply 49–62
81. Bartzokis G, Lu PH, Mintz J (2004) Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer’s disease. J Alzheimer’s Dis JAD 6(6 Suppl):S53–59
82. Bartzokis G, Lu PH, Tishler TA, Fong SM, Oluwadara B, Finn JP, Huang D, Bordelon Y et al (2007) Myelin breakdown and iron changes in Huntington’s disease: pathogenesis and treatment implications. Neurochem Res 32(10):1655–1664. doi:10.1007/s11064-007-9352-7
83. Zakin MM, Baron B, Guillou F (2002) Regulation of the tissue-specific expression of transferrin gene. Dev Neurosci 24(2-3):222–226
84. Puntarulo S (2005) Iron, oxidative stress and human health. Mol Asp Med 26(4–5):299–312. doi:10.1016/j.mam.2005.07.001
85. Grune T, Jung T, Merker K, Davies KJ (2004) Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease. Int J Biochem Cell Biol 36(12):2519–2530. doi:10.1016/j.biocel.2004.04.020
86. Bendlin BB, Carlsson CM, Johnson SC, Zetterberg H, Blennow K, Willette AA, Okonkwo OC, Sodhi A et al (2012) CSF T-Tau/Abeta42 predicts white matter microstructure in healthy adults at risk for Alzheimer’s disease. PLoS ONE 7(6):e37720. doi:10.1371/journal.pone.0037720
87. Back SA, Kroenke CD, Sherman LS, Lawrence G, Gong X, Taber EN, Sonnen JA, Larson EB et al (2011) White matter lesions defined by diffusion tensor imaging in older adults. Ann Neurol 70(3):465–476. doi:10.1002/ana.22484
88. Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, Salat DH (2006) Diffusion tensor imaging in presymptomatic and early Huntington’s disease: selective white matter pathology and its relationship to clinical measures. Mov Disord Off J Mov Disord Soc 21(9):1317–1325. doi:10.1002/mds.20979
89. Mitew S, Kirkcaldie MT, Halliday GM, Shepherd CE, Vickers JC, Dickson TC (2010) Focal demyelination in Alzheimer’s disease and transgenic mouse models. Acta Neuropathol 119(5):567–577. doi:10.1007/s00401-010-0657-2
90. Schmued LC, Raymick J, Paule MG, Dumas M, Sarkar S (2013) Characterization of myelin pathology in the hippocampal complex of a transgenic mouse model of Alzheimer’s disease. Curr Alzheimer Res 10(1):30–37
91. Behrendt G, Baer K, Buffo A, Curtis MA, Faull RL, Rees MI, Gotz M, Dimou L (2013) Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men. Glia 61(2):273–286. doi:10.1002/glia.22432
92. Desai MK, Mastrangelo MA, Ryan DA, Sudol KL, Narrow WC, Bowers WJ (2010) Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target. Am J Pathol 177(3):1422–1435. doi:10.2353/ajpath.2010.100087
93. Horiuchi M, Maezawa I, Itoh A, Wakayama K, Jin LW, Itoh T, Decarli C (2012) Amyloid beta1-42 oligomer inhibits myelin sheet formation in vitro. Neurobiol Aging 33(3):499–509. doi:10.1016/j.neurobiolaging.2010.05.007
94. Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, Rothstein JD, Bergles DE (2013) Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16(5):571–579. doi:10.1038/nn.3357
95. Philips T, Bento-Abreu A, Nonneman A, Haeck W, Staats K, Geelen V, Hersmus N, Kusters B et al (2013) Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain J Neurol 136(Pt 2):471–482. doi:10.1093/brain/aws339
96. Graham JG, Oppenheimer DR (1969) Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry 32(1):28–34
97. Stefanova N, Bucke P, Duerr S, Wenning GK (2009) Multiple system atrophy: an update. Lancet Neurol 8(12):1172–1178. doi:10.1016/S1474-4422(09)70288-1
98. Bower JH, Maraganore DM, McDonnell SK, Rocca WA (1997) Incidence of progressive supranuclear palsy and multiple system atrophy in Olmsted County, Minnesota, 1976 to 1990. Neurology 49(5):1284–1288
99. Wenning GK, Colosimo C, Geser F, Poewe W (2004) Multiple system atrophy. Lancet Neurol 3(2):93–103
100. Wenning GK, Geser F, Krismer F, Seppi K, Duerr S, Boesch S, Kollensperger M, Goebel G et al (2013) The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 12(3):264–274. doi:10.1016/S1474-4422(12)70327-7
101. Collaboration M-SAR (2013) Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med 369(3):233–244. doi:10.1056/NEJMoa1212115
102. Chen YP, Zhao B, Cao B, Song W, Guo X, Wei QQ, Yang Y, Yuan LX et al (2014) Mutation scanning of the COQ2 gene in ethnic Chinese patients with multiple-system atrophy. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2014.09.010
103. Ogaki K, Fujioka S, Heckman MG, Rayaprolu S, Soto-Ortolaza AI, Labbe C, Walton RL, Lorenzo-Betancor O et al (2014) Analysis of COQ2 gene in multiple system atrophy. Mol Neurodegener 9:44. doi:10.1186/1750-1326-9-44
104. Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, Healy DG, Wood NW et al (2004) The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain J Neurol 127(Pt 12):2657–2671. doi:10.1093/brain/awh303
105. Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP (1997) Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord Off J Mov Disord Soc 12(2):133–147. doi:10.1002/mds.870120203
106. Ozawa T (2007) Morphological substrate of autonomic failure and neurohormonal dysfunction in multiple system atrophy: impact on determining phenotype spectrum. Acta Neuropathol 114(3):201–211. doi:10.1007/s00401-007-0254-1
107. 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(3):735–744. doi:10.1016/S0002-9440(10)65617-9
108. 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(1-3):79–100
109. Song YJ, Lundvig DM, Huang Y, Gai WP, Blumbergs PC, Hojrup P, Otzen D, Halliday GM et al (2007) p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171(4):1291–1303. doi:10.2353/ajpath.2007.070201
110. Brooks DJ, Seppi K, Neuroimaging Working Group on MSA (2009) Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord Off J Mov Disord Soc 24(7):949–964. doi:10.1002/mds.22413
111. Prodoehl J, Li H, Planetta PJ, Goetz CG, Shannon KM, Tangonan R, Comella CL, Simuni T et al (2013) Diffusion tensor imaging of Parkinson’s disease, atypical parkinsonism, and essential tremor. Mov Disord Off J Mov Disord Soc 28(13):1816–1822. doi:10.1002/mds.25491
112. Blain CR, Barker GJ, Jarosz JM, Coyle NA, Landau S, Brown RG, Chaudhuri KR, Simmons A et al (2006) Measuring brain stem and cerebellar damage in parkinsonian syndromes using diffusion tensor MRI. Neurology 67(12):2199–2205. doi:10.1212/01.wnl.0000249307.59950.f8
113. Paviour DC, Thornton JS, Lees AJ, Jager HR (2007) Diffusion-weighted magnetic resonance imaging differentiates Parkinsonian variant of multiple-system atrophy from progressive supranuclear palsy. Mov Disord Off J Mov Disord Soc 22(1):68–74. doi:10.1002/mds.21204
114. Schocke MF, Seppi K, Esterhammer R, Kremser C, Jaschke W, Poewe W, Wenning GK (2002) Diffusion-weighted MRI differentiates the Parkinson variant of multiple system atrophy from PD. Neurology 58(4):575–580
115. Shiga K, Yamada K, Yoshikawa K, Mizuno T, Nishimura T, Nakagawa M (2005) Local tissue anisotropy decreases in cerebellopetal fibers and pyramidal tract in multiple system atrophy. J Neurol 252(5):589–596. doi:10.1007/s00415-005-0708-0
116. Ubhi K, Low P, Masliah E (2011) Multiple system atrophy: a clinical and neuropathological perspective. Trends Neurosci 34(11):581–590. doi:10.1016/j.tins.2011.08.003
117. Salvesen L, Ullerup BH, Sunay FB, Brudek T, Lokkegaard A, Agander TK, Winge K, Pakkenberg B (2014) Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy—a stereological study. Neurobiol Dis 74C:104–113. doi:10.1016/j.nbd.2014.11.008
118. Ishizawa K, Komori T, Arai N, Mizutani T, Hirose T (2008) Glial cytoplasmic inclusions and tissue injury in multiple system atrophy: a quantitative study in white matter (olivopontocerebellar system) and gray matter (nigrostriatal system). Neuropathol Off J Jpn Soc Neuropathol 28(3):249–257. doi:10.1111/j.1440-1789.2007.00855.x
119. Song YJ, Halliday GM, Holton JL, Lashley T, O’Sullivan SS, McCann H, Lees AJ, Ozawa T et al (2009) Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol 68(10):1073–1083. doi:10.1097/NEN.0b013e3181b66f1b
120. Ishizawa K, Komori T, Sasaki S, Arai N, Mizutani T, Hirose T (2004) Microglial activation parallels system degeneration in multiple system atrophy. J Neuropathol Exp Neurol 63(1):43–52
121. Papp MI, Lantos PL (1992) Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy. J Neurol Sci 107(2):172–182
122. Papp MI, Lantos PL (1994) The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology. Brain J Neurol 117(Pt 2):235–243
123. Lantos PL, Papp MI (1994) Cellular pathology of multiple system atrophy: a review. J Neurol Neurosurg Psychiatry 57(2):129–133
124. Halliday GM, Holton JL, Revesz T, Dickson DW (2011) Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122(2):187–204. doi:10.1007/s00401-011-0852-9
125. Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M (1997) The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol 93(6):585–591
126. Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251(3):205–208
127. Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T et al (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44(3):415–422. doi:10.1002/ana.410440324
128. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249(2–3):180–182
129. McCann H, Stevens CH, Cartwright H, Halliday GM (2014) alpha-Synucleinopathy phenotypes. Parkinsonism Relat Disord 20(Suppl 1):S62–67. doi:10.1016/S1353-8020(13)70017-8
130. Nakamura S, Kawamoto Y, Nakano S, Akiguchi I, Kimura J (1998) Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy. J Neuropathol Exp Neurol 57(7):690–698
131. Kato S, Shinozawa T, Takikawa M, Kato M, Hirano A, Awaya A, Ohama E (2000) Midkine, a new neurotrophic factor, is present in glial cytoplasmic inclusions of multiple system atrophy brains. Acta Neuropathol 100(5):481–489
132. Nakamura S, Kawamoto Y, Nakano S, Akiguchi I (2000) Expression of the endocytosis regulatory proteins Rab5 and Rabaptin-5 in glial cytoplasmic inclusions from brains with multiple system atrophy. Clin Neuropathol 19(2):51–56
133. Honjyo Y, Kawamoto Y, Nakamura S, Nakano S, Akiguchi I (2001) P39 immunoreactivity in glial cytoplasmic inclusions in brains with multiple system atrophy. Acta Neuropathol 101(3):190–194
134. Iwata A, Miura S, Kanazawa I, Sawada M, Nukina N (2001) alpha-Synuclein forms a complex with transcription factor Elk-1. J Neurochem 77(1):239–252
135. Piao YS, Hayashi S, Hasegawa M, Wakabayashi K, Yamada M, Yoshimoto M, Ishikawa A, Iwatsubo T et al (2001) Co-localization of alpha-synuclein and phosphorylated tau in neuronal and glial cytoplasmic inclusions in a patient with multiple system atrophy of long duration. Acta Neuropathol 101(3):285–293
136. Kawamoto Y, Akiguchi I, Nakamura S, Budka H (2002) Accumulation of 14-3-3 proteins in glial cytoplasmic inclusions in multiple system atrophy. Ann Neurol 52(6):722–731. doi:10.1002/ana.10361
137. Sasaki K, Doh-ura K, Wakisaka Y, Iwaki T (2002) Clusterin/apolipoprotein J is associated with cortical Lewy bodies: immunohistochemical study in cases with alpha-synucleinopathies. Acta Neuropathol 104(3):225–230. doi:10.1007/s00401-002-0546-4
138. Wakabayashi K, Engelender S, Tanaka Y, Yoshimoto M, Mori F, Tsuji S, Ross CA, Takahashi H (2002) Immunocytochemical localization of synphilin-1, an alpha-synuclein-associated protein, in neurodegenerative disorders. Acta Neuropathol 103(3):209–214. doi:10.1007/s004010100451
139. Hishikawa N, Niwa J, Doyu M, Ito T, Ishigaki S, Hashizume Y, Sobue G (2003) Dorfin localizes to the ubiquitylated inclusions in Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis. Am J Pathol 163(2):609–619
140. Pountney DL, Chegini F, Shen X, Blumbergs PC, Gai WP (2005) SUMO-1 marks subdomains within glial cytoplasmic inclusions of multiple system atrophy. Neurosci Lett 381(1–2):74–79. doi:10.1016/j.neulet.2005.02.013
141. Pountney DL, Treweek TM, Chataway T, Huang Y, Chegini F, Blumbergs PC, Raftery MJ, Gai WP (2005) Alpha B-crystallin is a major component of glial cytoplasmic inclusions in multiple system atrophy. Neurotox Res 7(1–2):77–85
142. Tanji K, Mori F, Kakita A, Zhang H, Kito K, Kamitani T, Takahashi H, Wakabayashi K (2007) Immunohistochemical localization of NUB1, a synphilin-1-binding protein, in neurodegenerative disorders. Acta Neuropathol 114(4):365–371. doi:10.1007/s00401-007-0238-1
143. Taylor JM, Song YJ, Huang Y, Farrer MJ, Delatycki MB, Halliday GM, Lockhart PJ (2007) Parkin Co-Regulated Gene (PACRG) is regulated by the ubiquitin-proteasomal system and is present in the pathological features of Parkinsonian diseases. Neurobiol Dis 27(2):238–247. doi:10.1016/j.nbd.2007.04.014
144. Honjo Y, Shirakashi Y, Kawamoto Y, Akiguchi I (2008) Anti-DARPP32 antibody-immunopositive inclusions in the brain of patients with multiple system atrophy. Clin Neuropathol 27(5):309–316
145. Kawamoto Y, Kobayashi Y, Suzuki Y, Inoue H, Tomimoto H, Akiguchi I, Budka H, Martins LM et al (2008) Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains with alpha-synucleinopathies. J Neuropathol Exp Neurol 67(10):984–993. doi:10.1097/NEN.0b013e31818809f4
146. Honjo Y, Ito H, Horibe T, Takahashi R, Kawakami K (2011) Protein disulfide isomerase immunopositive glial cytoplasmic inclusions in patients with multiple system atrophy. Int J Neurosci 121(10):543–550. doi:10.3109/00207454.2011.585440
147. Pountney DL, Dickson TC, Power JH, Vickers JC, West AJ, Gai WP (2011) Association of metallothionein-III with oligodendroglial cytoplasmic inclusions in multiple system atrophy. Neurotox Res 19(1):115–122. doi:10.1007/s12640-009-9146-6
148. Chiba Y, Takei S, Kawamura N, Kawaguchi Y, Sasaki K, Hasegawa-Ishii S, Furukawa A, Hosokawa M et al (2012) Immunohistochemical localization of aggresomal proteins in glial cytoplasmic inclusions in multiple system atrophy. Neuropathol Appl Neurobiol 38(6):559–571. doi:10.1111/j.1365-2990.2011.01229.x
149. Odagiri S, Tanji K, Mori F, Kakita A, Takahashi H, Wakabayashi K (2012) Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in alpha-synucleinopathy. Acta Neuropathol 124(2):173–186. doi:10.1007/s00401-012-0975-7
150. Zhao T, Severijnen LA, van der Weiden M, Zheng PP, Oostra BA, Hukema RK, Willemsen R, Kros JM et al (2013) FBXO7 immunoreactivity in alpha-synuclein-containing inclusions in Parkinson disease and multiple system atrophy. J Neuropathol Exp Neurol 72(6):482–488. doi:10.1097/NEN.0b013e318293c586
151. Kawamoto Y, Ito H, Ihara M, Takahashi R (2014) XIAP immunoreactivity in glial and neuronal cytoplasmic inclusions in multiple system atrophy. Clin Neuropathol 33(1):76–83. doi:10.5414/NP300610
152. Gai WP, Pountney DL, Power JH, Li QX, Culvenor JG, McLean CA, Jensen PH, Blumbergs PC (2003) alpha-Synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy. Exp Neurol 181(1):68–78
153. Lindersson E, Lundvig D, Petersen C, Madsen P, Nyengaard JR, Hojrup P, Moos T, Otzen D et al (2005) p25alpha Stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies. J Biol Chem 280(7):5703–5715. doi:10.1074/jbc.M410409200
154. Kovacs GG, Gelpi E, Lehotzky A, Hoftberger R, Erdei A, Budka H, Ovadi J (2007) The brain-specific protein TPPP/p25 in pathological protein deposits of neurodegenerative diseases. Acta Neuropathol 113(2):153–161. doi:10.1007/s00401-006-0167-4
155. Don AS, Hsiao JH, Bleasel JM, Couttas TA, Halliday GM, Kim W (2014) Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun 2(1):150. doi:10.1186/s40478-014-0150-6
156. 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 Park Dis 3(3):331–339. doi:10.3233/JPD-130203
157. Makioka K, Yamazaki T, Fujita Y, Takatama M, Nakazato Y, Okamoto K (2010) Involvement of endoplasmic reticulum stress defined by activated unfolded protein response in multiple system atrophy. J Neurol Sci 297(1–2):60–65. doi:10.1016/j.jns.2010.06.019
158. 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(10):1084–1091. doi:10.1097/NEN.0b013e3181b67678
159. Duda JE, Giasson BI, Gur TL, Montine TJ, Robertson D, Biaggioni I, Hurtig HI, Stern MB et al (2000) Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy. J Neuropathol Exp Neurol 59(9):830–841
160. Dickson DW, Liu W, Hardy J, Farrer M, Mehta N, Uitti R, Mark M, Zimmerman T et al (1999) Widespread alterations of alpha-synuclein in multiple system atrophy. Am J Pathol 155(4):1241–1251
161. Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, Jakala P, Beyreuther K, Masters CL et al (2001) The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76(1):87–96
162. Pountney DL, Lowe R, Quilty M, Vickers JC, Voelcker NH, Gai WP (2004) Annular alpha-synuclein species from purified multiple system atrophy inclusions. J Neurochem 90(2):502–512. doi:10.1111/j.1471-4159.2004.02533.x
163. Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ et al (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290(5493):985–989
164. Jin H, Ishikawa K, Tsunemi T, Ishiguro T, Amino T, Mizusawa H (2008) Analyses of copy number and mRNA expression level of the alpha-synuclein gene in multiple system atrophy. J Med Dent Sci 55(1):145–153
165. Miller DW, Johnson JM, Solano SM, Hollingsworth ZR, Standaert DG, Young AB (2005) Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J Neural Transm 112(12):1613–1624. doi:10.1007/s00702-005-0378-1
166. 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(6):964–970. doi:10.1002/glia.22653
167. Solano SM, Miller DW, Augood SJ, Young AB, Penney JB Jr (2000) Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson’s disease. Ann Neurol 47(2):201–210
168. Ozawa T, Okuizumi K, Ikeuchi T, Wakabayashi K, Takahashi H, Tsuji S (2001) Analysis of the expression level of alpha-synuclein mRNA using postmortem brain samples from pathologically confirmed cases of multiple system atrophy. Acta Neuropathol 102(2):188–190
169. Lincoln SJ, Ross OA, Milkovic NM, Dickson DW, Rajput A, Robinson CA, Papapetropoulos S, Mash DC et al (2007) Quantitative PCR-based screening of alpha-synuclein multiplication in multiple system atrophy. Parkinsonism Relat Disord 13(6):340–342. doi:10.1016/j.parkreldis.2006.12.005
170. Ozawa T, Healy DG, Abou-Sleiman PM, Ahmadi KR, Quinn N, Lees AJ, Shaw K, Wullner U et al (2006) The alpha-synuclein gene in multiple system atrophy. J Neurol Neurosurg Psychiatry 77(4):464–467. doi:10.1136/jnnp.2005.073528
171. Ozawa T, Takano H, Onodera O, Kobayashi H, Ikeuchi T, Koide R, Okuizumi K, Shimohata T et al (1999) No mutation in the entire coding region of the alpha-synuclein gene in pathologically confirmed cases of multiple system atrophy. Neurosci Lett 270(2):110–112
172. Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D, Melchers A, Paudel R et al (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65(5):610–614. doi:10.1002/ana.21685
173. Al-Chalabi A, Durr A, Wood NW, Parkinson MH, Camuzat A, Hulot JS, Morrison KE, Renton A et al (2009) Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy. PLoS ONE 4(9):e7114. doi:10.1371/journal.pone.0007114
174. Ettle B, Reiprich S, Deusser J, Schlachetzki JC, Xiang W, Prots I, Masliah E, Winner B et al (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
175. Rockenstein E, Ubhi K, Inglis C, Mante M, Patrick C, Adame A, Masliah E (2012) Neuronal to oligodendroglial alpha-synuclein redistribution in a double transgenic model of multiple system atrophy. Neuroreport 23(4):259–264. doi:10.1097/WNR.0b013e3283509842
176. Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E (2014) Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 62(3):387–398. doi:10.1002/glia.22611
177. Kisos H, Ben-Gedalya T, Sharon R (2013) The clathrin-dependent localization of dopamine transporter to surface membranes is affected by alpha-synuclein. J Mol Neurosci MN. doi:10.1007/s12031-013-0118-1
178. Kisos H, Pukass K, Ben-Hur T, Richter-Landsberg C, Sharon R (2012) Increased neuronal alpha-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling alpha-synucleinopathies. PLoS ONE 7(10):e46817. doi:10.1371/journal.pone.0046817
179. Tsuboi K, Grzesiak JJ, Bouvet M, Hashimoto M, Masliah E, Shults CW (2005) Alpha-synuclein overexpression in oligodendrocytic cells results in impaired adhesion to fibronectin and cell death. Mol Cell Neurosci 29(2):259–268. doi:10.1016/j.mcn.2005.03.001
180. Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM (2000) alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62(1):9–14
181. Konno M, Hasegawa T, Baba T, Miura E, Sugeno N, Kikuchi A, Fiesel FC, Sasaki T et al (2012) Suppression of dynamin GTPase decreases alpha-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy. Mol Neurodegener 7:38. doi:10.1186/1750-1326-7-38
182. 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(3):263–273. doi:10.1111/j.1750-3639.2012.00637.x
183. May VE, Ettle B, Poehler AM, Nuber S, Ubhi K, Rockenstein E, Winner B, Wegner M et al (2014) alpha-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiol Aging 35(10):2357–2368. doi:10.1016/j.neurobiolaging.2014.02.028
184. 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(6):847–859. doi:10.1016/j.neuron.2005.01.032
185. Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, Fuss B, Mallon B et al (2002) Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 3(6):583–588. doi:10.1093/embo-reports/kvf109
186. Shults CW, Rockenstein E, Crews L, Adame A, Mante M, Larrea G, Hashimoto M, Song D 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 Off J Soc Neurosci 25(46):10689–10699. doi:10.1523/JNEUROSCI.3527-05.2005
187. Ubhi K, Lee PH, Adame A, Inglis C, Mante M, Rockenstein E, Stefanova N, Wenning GK et al (2009) Mitochondrial inhibitor 3-nitroproprionic acid enhances oxidative modification of alpha-synuclein in a transgenic mouse model of multiple system atrophy. J Neurosci Res 87(12):2728–2739. doi:10.1002/jnr.22089
188. Krismer F, Wenning GK, Li Y, Poewe W, Stefanova N (2013) Intact olfaction in a mouse model of multiple system atrophy. PLoS ONE 8(5):e64625. doi:10.1371/journal.pone.0064625
189. Kuzdas D, Stemberger S, Gaburro S, Stefanova N, Singewald N, Wenning GK (2013) Oligodendroglial alpha-synucleinopathy and MSA-like cardiovascular autonomic failure: experimental evidence. Exp Neurol 247:531–536. doi:10.1016/j.expneurol.2013.02.002
190. Tank J, da Costa-Goncalves AC, Kamer I, Qadri F, Ubhi K, Rockenstein E, Diedrich A, Masliah E, Gross V, Jordan J (2014) Preserved functional autonomic phenotype in adult mice overexpressing moderate levels of human alpha-synuclein in oligodendrocytes. Physiol. Rep. 2 (11). doi:10.14814/phy2.12209
191. Boudes M, Uvin P, Pinto S, Voets T, Fowler CJ, Wenning GK, De Ridder D, Stefanova N (2013) Bladder dysfunction in a transgenic mouse model of multiple system atrophy. Mov Disord Off J Mov Disord Soc 28(3):347–355. doi:10.1002/mds.25336
192. Flabeau O, Meissner WG, Ozier A, Berger P, Tison F, Fernagut PO (2014) Breathing variability and brainstem serotonergic loss in a genetic model of multiple system atrophy. Mov Disord Off J Mov Disord Soc 29(3):388–395. doi:10.1002/mds.25804
193. Stemberger S, Poewe W, Wenning GK, Stefanova N (2010) Targeted overexpression of human alpha-synuclein in oligodendroglia induces lesions linked to MSA-like progressive autonomic failure. Exp Neurol 224(2):459–464. doi:10.1016/j.expneurol.2010.05.008
194. Suzuki Y, Jin C, Yazawa I (2014) Cystatin C triggers neuronal degeneration in a model of multiple system atrophy. Am J Pathol 184(3):790–799. doi:10.1016/j.ajpath.2013.11.018
195. 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(1):51–65. doi:10.1007/s00401-012-0977-5
196. Schwarz L, Goldbaum O, Bergmann M, Probst-Cousin S, Richter-Landsberg C (2012) Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes. J Mol Neurosci MN 47(2):256–266. doi:10.1007/s12031-012-9733-5
197. Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, Wenning GK (2005) Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol 166(3):869–876
198. Pukass K, Richter-Landsberg C (2014) Oxidative stress promotes uptake, accumulation, and oligomerization of extracellular alpha-synuclein in oligodendrocytes. J Mol Neurosci MN 52(3):339–352. doi:10.1007/s12031-013-0154-x
199. Riedel M, Goldbaum O, Wille M, Richter-Landsberg C (2011) Membrane lipid modification by docosahexaenoic acid (DHA) promotes the formation of alpha-synuclein inclusion bodies immunopositive for SUMO-1 in oligodendroglial cells after oxidative stress. J Mol Neurosci MN 43(3):290–302. doi:10.1007/s12031-010-9439-5
200. Brand A, Bauer NG, Hallott A, Goldbaum O, Ghebremeskel K, Reifen R, Richter-Landsberg C (2010) Membrane lipid modification by polyunsaturated fatty acids sensitizes oligodendroglial OLN-93 cells against oxidative stress and promotes up-regulation of heme oxygenase-1 (HSP32). J Neurochem 113(2):465–476. doi:10.1111/j.1471-4159.2010.06611.x
201. Riedel M, Goldbaum O, Richter-Landsberg C (2009) alpha-Synuclein promotes the recruitment of tau to protein inclusions in oligodendroglial cells: effects of oxidative and proteolytic stress. J Mol Neurosci MN 39(1–2):226–234. doi:10.1007/s12031-009-9190-y
202. Kragh CL, Fillon G, Gysbers A, Hansen HD, Neumann M, Richter-Landsberg C, Haass C, Zalc B et al (2013) FAS-dependent cell death in alpha-synuclein transgenic oligodendrocyte models of multiple system atrophy. PLoS ONE 8(1):e55243. doi:10.1371/journal.pone.0055243
203. Kragh CL, Lund LB, Febbraro F, Hansen HD, Gai WP, El-Agnaf O, Richter-Landsberg C, Jensen PH (2009) Alpha-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells. J Biol Chem 284(15):10211–10222. doi:10.1074/jbc.M809671200
204. Stefanova N, Georgievska B, Eriksson H, Poewe W, Wenning GK (2012) Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Neurotox Res 21(4):393–404. doi:10.1007/s12640-011-9294-3
205. Stefanova N, Puschban Z, Fernagut PO, Brouillet E, Tison F, Reindl M, Jellinger KA, Poewe W et al (2003) Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral degeneration (multiple system atrophy). Acta Neuropathol 106(2):157–166. doi:10.1007/s00401-003-0717-y
206. Ubhi K, Rockenstein E, Mante M, Inglis C, Adame A, Patrick C, Masliah E (2010) Alpha-synuclein deficient mice are resistant to toxin-induced multiple system atrophy. Neuroreport 21(6):457–462. doi:10.1097/WNR.0b013e328338ba6b
207. Pfeiffer SE, Warrington AE, Bansal R (1993) The oligodendrocyte and its many cellular processes. Trends Cell Biol 3(6):191–197
208. Ubhi K, Rockenstein E, Mante M, Inglis C, Adame A, Patrick C, Whitney K, Masliah E (2010) Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors. J Neurosci Off J Soc Neurosci 30(18):6236–6246. doi:10.1523/JNEUROSCI.0567-10.2010
209. Ubhi K, Inglis C, Mante M, Patrick C, Adame A, Spencer B, Rockenstein E, May V et al (2012) Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of alpha-synucleinopathy. Exp Neurol 234(2):405–416. doi:10.1016/j.expneurol.2012.01.008
210. Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64(3):239–246. doi:10.1002/ana.21465
211. Schwarz J, Weis S, Kraft E, Tatsch K, Bandmann O, Mehraein P, Vogl T, Oertel WH (1996) Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy. J Neurol Neurosurg Psychiatry 60(1):98–101
212. Stefanova N, Reindl M, Neumann M, Kahle PJ, Poewe W, Wenning GK (2007) Microglial activation mediates neurodegeneration related to oligodendroglial alpha-synucleinopathy: implications for multiple system atrophy. Mov Disord Off J Mov Disord Soc 22(15):2196–2203. doi:10.1002/mds.21671
213. Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, Wenning GK, Stefanova N (2013) Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61(3):349–360. doi:10.1002/glia.22437