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Acta Neuropathologica

, Volume 138, Issue 1, pp 1–21 | Cite as

α-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease

  • Zachary A. Sorrentino
  • Benoit I. Giasson
  • Paramita ChakrabartyEmail author
Review

Abstract

α-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders referred to as α-synucleinopathies. Though α-synuclein is expressed predominantly in neurons, α-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. How and why α-synuclein ends up in the astrocytes and the consequences of this dysfunctional proteostasis in immune cells is a major area of research that can have far-reaching implications for future immunobiotherapies in α-synucleinopathies. Accumulation of aggregated α-synuclein can disrupt astrocyte function in general and, more importantly, can contribute to neurodegeneration in α-synucleinopathies through various pathways. Here, we summarize our current knowledge on how astrocytic α-synucleinopathy affects CNS function in health and disease and propose a model of neuroglial connectome altered by α-synuclein proteostasis that might be amenable to immune-based therapies.

Keywords

αSyn 3H11 α-Synuclein Lewy body Glial cytoplasmic inclusion Neurodegeneration Exosome Tunneling nanotube Transmission Astrocyte heterogeneity NAC domain Therapy 

Abbreviations

αSyn

α-Synuclein

AKT

‘AK’ thymoma

ARE

Anti-oxidant response element

CNS

Central nervous system

CDNF

Cerebral dopamine neurotrophic factor

CSF

Cerebrospinal fluid

DAMP

Damage associated molecular pattern

DLB

Dementia with Lewy bodies

DNTC

Diffuse neurofibrillary tangles with calcification

EM

Electron microscope

FA

Formic acid

Foxa1

Forkhead box A1

GABA

Gamma-amino butyric acid

GDNF

Glial cell line-derived neurotrophic factor

GCI

Glial cytoplasmic inclusions

GFAP

Glial fibrillary acidic protein

GLP1R

Glucagon-like peptide-1 receptor

GBA

Glucocerebrosidase

H&E

Hematoxylin and eosin staining

HLA-DR

Human leukocyte antigen-DR isotype

LBVAD

Lewy body variant Alzheimer's disease

MHC-II

Major histocompatibility complex class II

MMP

Matrix metalloproteinase

MANF

Mesencephalic astrocyte-derived neurotrophic factor

iLBD

Incidental Lewy body diseases

Keap1

Kelch-like ECH-associated protein 1

LRRK2

Leucine-rich repeat kinase 2

LB

Lewy bodies

LN

Lewy neurites

MSA

Multiple system atrophy

NQO1

NAD(P)H quinone dehydrogenase 1

NCI

Neuronal cytoplasmic inclusions

NRTN

Neurturin

NAC

Non-amyloid β component

Nrf2

Nuclear factor erythroid 2-like 2

NFκB

Nuclear factor κ-light-chain-enhancer of activated B cells

Nurr1/NR4A2

Nuclear receptor subfamily 4, group A, member 2

PD

Parkinson’s disease

PARK

Parkinson’s disease-associated gene

PDD

PD with dementia

PI3K

Phosphatidylinositol 3-kinase

PDGFβ

Platelet-derived growth factor β

PET

Positron-emission tomography

pSer129

Phosphorylated serine 129

PINK1

Pten-induced putative kinase 1

ROS

Reactive oxygen species

SLA

Star like astrocyte

SNpc

Substantia Nigra pars compacta

SQSTM1

Sequestosome 1

Thy-1

Thymocyte differentiation antigen 1

TLR

Toll-like receptor

TNT

Tunneling nanotube

Notes

Acknowledgements

This work was supported by NIH Grant NS099738 (PC) and NS089622 (BIG). We acknowledge the University of Florida Neuromedicine Brain Bank for access to human tissue samples.

References

  1. 1.
    Abounit S, Bousset L, Loria F, Zhu S, de Chaumont F, Pieri L et al (2016) Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes. EMBO J 35:2120–2138.  https://doi.org/10.15252/embj.201593411 Google Scholar
  2. 2.
    Ahn T-B, Langston JW, Aachi VR, Dickson DW (2012) Relationship of neighboring tissue and gliosis to alpha-synuclein pathology in a fetal transplant for Parkinson’s disease. Am J Neurodegener Dis 1:49–59Google Scholar
  3. 3.
    Allen NJ, Eroglu C (2017) Cell biology of astrocyte-synapse interactions. Neuron 96:697–708.  https://doi.org/10.1016/j.neuron.2017.09.056 Google Scholar
  4. 4.
    Allen Reish HE, Standaert DG (2015) Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis 5:1–19.  https://doi.org/10.3233/JPD-140491 Google Scholar
  5. 5.
    Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752.  https://doi.org/10.1074/jbc.M600933200 Google Scholar
  6. 6.
    Angelova PR, Ludtmann MHR, Horrocks MH, Negoda A, Cremades N, Klenerman D et al (2016) Ca2 + is a key factor in alpha-synuclein-induced neurotoxicity. J Cell Sci 129:1792–1801.  https://doi.org/10.1242/jcs.180737 Google Scholar
  7. 7.
    Arai T, Uéda K, Ikeda K, Akiyama H, Haga C, Kondo H et al (1999) Argyrophilic glial inclusions in the midbrain of patients with Parkinson’s disease and diffuse Lewy body disease are immunopositive for NACP/alpha-synuclein. Neurosci Lett 259:83–86Google Scholar
  8. 8.
    Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL (2014) Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol 206:655–670.  https://doi.org/10.1083/jcb.201401070 Google Scholar
  9. 9.
    Athauda D, Foltynie T (2016) The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov Today 21:802–818.  https://doi.org/10.1016/j.drudis.2016.01.013 Google Scholar
  10. 10.
    Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K et al (2017) Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet 390:1664–1675.  https://doi.org/10.1016/S0140-6736(17)31585-4 Google Scholar
  11. 11.
    Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Ell P et al (2015) Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis 4:337–344.  https://doi.org/10.3233/JPD-140364 Google Scholar
  12. 12.
    Baig F, Lawton M, Rolinski M, Ruffmann C, Nithi K, Evetts SG et al (2015) Delineating nonmotor symptoms in early Parkinson’s disease and first-degree relatives. Mov Disord 30:1759–1766.  https://doi.org/10.1002/mds.26281 Google Scholar
  13. 13.
    Barker RA, Williams-Gray CH (2016) Review: the spectrum of clinical features seen with alpha synuclein pathology. Neuropathol Appl Neurobiol 42:6–19.  https://doi.org/10.1111/nan.12303 Google Scholar
  14. 14.
    Barrenschee M, Zorenkov D, Böttner M, Lange C, Cossais F, Scharf AB et al (2017) Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathol Commun 5:1.  https://doi.org/10.1186/s40478-016-0408-2 Google Scholar
  15. 15.
    Bartels T, Choi JG, Selkoe DJ (2011) α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477:107–110.  https://doi.org/10.1038/nature10324 Google Scholar
  16. 16.
    Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Arizona Parkinson’s Disease Consortium et al (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702.  https://doi.org/10.1007/s00401-010-0664-3 Google Scholar
  17. 17.
    Bellucci A, Collo G, Sarnico I, Battistin L, Missale C, Spano P (2008) Alpha-synuclein aggregation and cell death triggered by energy deprivation and dopamine overload are counteracted by D 2 D 3 receptor activation. J Neurochem 106:560–577.  https://doi.org/10.1111/j.1471-4159.2008.05406.x Google Scholar
  18. 18.
    Bertoncini CW, Jung Y-S, Fernandez CO, Hoyer W, Griesinger C, Jovin TM et al (2005) Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc Natl Acad Sci USA 102:1430–1435.  https://doi.org/10.1073/pnas.0407146102 Google Scholar
  19. 19.
    Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 202:17–20Google Scholar
  20. 20.
    Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, van Swieten JC et al (2003) DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 24:159–160.  https://doi.org/10.1007/s10072-003-0108-0 Google Scholar
  21. 21.
    Booth HDE, Hirst WD, Wade-Martins R (2017) The role of astrocyte dysfunction in Parkinson’s disease pathogenesis. Trends Neurosci 40:358–370.  https://doi.org/10.1016/j.tins.2017.04.001 Google Scholar
  22. 22.
    Braak H, Sastre M, Del Tredici K (2007) Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol 114:231–241.  https://doi.org/10.1007/s00401-007-0244-3 Google Scholar
  23. 23.
    Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen-Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211Google Scholar
  24. 24.
    Braak H, de Vos RAI, Bohl J, Del Tredici K (2006) Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72.  https://doi.org/10.1016/j.neulet.2005.11.012 Google Scholar
  25. 25.
    Braidy N, Gai W-P, Xu YH, Sachdev P, Guillemin GJ, Jiang X-M et al (2013) Uptake and mitochondrial dysfunction of alpha-synuclein in human astrocytes, cortical neurons and fibroblasts. Transl Neurodegener 2:20.  https://doi.org/10.1186/2047-9158-2-20 Google Scholar
  26. 26.
    Breydo L, Wu JW, Uversky VN (2012) α-Synuclein misfolding and Parkinson’s disease. Biochim Biophys Acta Mol Basis Dis 1822:261–285.  https://doi.org/10.1016/j.bbadis.2011.10.002 Google Scholar
  27. 27.
    Brück D, Wenning GK, Stefanova N, Fellner L (2016) Glia and alpha-synuclein in neurodegeneration: a complex interaction. Neurobiol Dis 85:262–274.  https://doi.org/10.1016/j.nbd.2015.03.003 Google Scholar
  28. 28.
    Brundin P, Dave KD, Kordower JH (2017) Therapeutic approaches to target alpha-synuclein pathology. Exp Neurol 298:225–235.  https://doi.org/10.1016/j.expneurol.2017.10.003 Google Scholar
  29. 29.
    Budnik V, Ruiz-Cañada C, Wendler F (2016) Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci 17:160–172.  https://doi.org/10.1038/nrn.2015.29 Google Scholar
  30. 30.
    Buell AK, Galvagnion C, Gaspar R, Sparr E, Vendruscolo M, Knowles TPJ et al (2014) Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation. Proc Natl Acad Sci USA 111:7671–7676.  https://doi.org/10.1073/pnas.1315346111 Google Scholar
  31. 31.
    Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S et al (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci 101:9103–9108.  https://doi.org/10.1073/pnas.0402959101 Google Scholar
  32. 32.
    Castagnet PI, Golovko MY, Barceló-Coblijn GC, Nussbaum RL, Murphy EJ (2005) Fatty acid incorporation is decreased in astrocytes cultured from alpha-synuclein gene-ablated mice. J Neurochem 94:839–849.  https://doi.org/10.1111/j.1471-4159.2005.03247.x Google Scholar
  33. 33.
    Cavaliere F, Cerf L, Dehay B, Ramos-Gonzalez P, De Giorgi F, Bourdenx M et al (2017) In vitro alpha-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Neurobiol Dis 103:101–112.  https://doi.org/10.1016/j.nbd.2017.04.011 Google Scholar
  34. 34.
    Chang D, Nalls MA, Hallgrímsdóttir IB, Hunkapiller J, van der Brug M, Cai F et al (2017) A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 49:1511–1516.  https://doi.org/10.1038/ng.3955 Google Scholar
  35. 35.
    Chavarría C, Rodríguez-Bottero S, Quijano C, Cassina P, Souza JM (2018) Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons. Biochem J 475:3153–3169.  https://doi.org/10.1042/BCJ20180297 Google Scholar
  36. 36.
    Chen P-C, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW et al (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: critical role for the astrocyte. Proc Natl Acad Sci USA 106:2933–2938.  https://doi.org/10.1073/pnas.0813361106 Google Scholar
  37. 37.
    Cheng SY, Trombetta LD (2004) The induction of amyloid precursor protein and alpha-synuclein in rat hippocampal astrocytes by diethyldithiocarbamate and copper with or without glutathione. Toxicol Lett 146:139–149Google Scholar
  38. 38.
    Choi I, Kim J, Jeong H-K, Kim B, Jou I, Park SM et al (2013) Pink1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced akt and increased p38 mapk activation, and downregulation of egfr. Glia 61:800–812.  https://doi.org/10.1002/glia.22475 Google Scholar
  39. 39.
    Chu CT, Zhu J, Dagda R (2007) Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress: implications for neurodegeneration and cell death. Autophagy 3:663–666Google Scholar
  40. 40.
    Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP-Y (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci 103:15091–15096.  https://doi.org/10.1073/pnas.0607260103 Google Scholar
  41. 41.
    Cobb CA, Cole MP (2015) Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis 84:4–21.  https://doi.org/10.1016/j.nbd.2015.04.020 Google Scholar
  42. 42.
    Darmanis S, Sloan SA, Zhang Y, Enge M, Caneda C, Shuer LM et al (2015) A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci USA 112:7285–7290.  https://doi.org/10.1073/pnas.1507125112 Google Scholar
  43. 43.
    Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T, Bjorklund A (2012) Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Sci Transl Med 4:163ra156.  https://doi.org/10.1126/scitranslmed.3004676 Google Scholar
  44. 44.
    Denzer I, Münch G, Friedland K (2016) Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds. Pharmacol Res 103:80–94.  https://doi.org/10.1016/j.phrs.2015.11.019 Google Scholar
  45. 45.
    Dhillon J-KS, Riffe C, Moore BD, Ran Y, Chakrabarty P, Golde TE et al (2017) A novel panel of α-synuclein antibodies reveal distinctive staining profiles in synucleinopathies. PLoS One 12:e0184731.  https://doi.org/10.1371/journal.pone.0184731 Google Scholar
  46. 46.
    Dieriks BV, Park TI-H, Fourie C, Faull RLM, Dragunow M, Curtis MA (2017) α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson’s disease patients. Sci Rep 7:42984.  https://doi.org/10.1038/srep42984 Google Scholar
  47. 47.
    Dossi E, Vasile F, Rouach N (2017) Human astrocytes in the diseased brain. Brain Res Bull.  https://doi.org/10.1016/j.brainresbull.2017.02.001 Google Scholar
  48. 48.
    Du F, Yu Q, Chen A, Chen D, Yan SS (2018) Astrocytes attenuate mitochondrial dysfunctions in human dopaminergic neurons derived from iPSC. Stem cell reports 10:366–374.  https://doi.org/10.1016/j.stemcr.2017.12.021 Google Scholar
  49. 49.
    Ejlerskov P, Rasmussen I, Nielsen TT, Bergström A-L, Tohyama Y, Jensen PH et al (2013) Tubulin polymerization-promoting protein (TPPP/p25α) promotes unconventional secretion of α-synuclein through exophagy by impairing autophagosome-lysosome fusion. J Biol Chem 288:17313–17335.  https://doi.org/10.1074/jbc.M112.401174 Google Scholar
  50. 50.
    Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH et al (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851.  https://doi.org/10.1523/JNEUROSCI.5699-09.2010 Google Scholar
  51. 51.
    Erustes AG, Stefani FY, Terashima JY, Stilhano RS, Monteforte PT, da Silva Pereira GJ et al (2018) Overexpression of α-synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis. J Neurosci Res 96:160–171.  https://doi.org/10.1002/jnr.24092 Google Scholar
  52. 52.
    Fathy YY, Jonker AJ, Oudejans E, de Jong FJJ, van Dam A-MW, Rozemuller AJM et al (2018) Differential insular cortex subregional vulnerability to α-synuclein pathology in Parkinson’s disease and dementia with Lewy bodies. Neuropathol Appl Neurobiol.  https://doi.org/10.1111/nan.12501 Google Scholar
  53. 53.
    Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W et al (2013) Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia 61:349–360.  https://doi.org/10.1002/glia.22437 Google Scholar
  54. 54.
    Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS et al (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164.  https://doi.org/10.1038/ncb748 Google Scholar
  55. 55.
    Fusco G, De Simone A, Gopinath T, Vostrikov V, Vendruscolo M, Dobson CM et al (2014) Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour. Nat Commun 5:3827.  https://doi.org/10.1038/ncomms4827 Google Scholar
  56. 56.
    Gan L, Johnson DA, Johnson JA (2010) Keap1-Nrf2 activation in the presence and absence of DJ-1. Eur J Neurosci 31:967–977.  https://doi.org/10.1111/j.1460-9568.2010.07138.x Google Scholar
  57. 57.
    Gan L, Vargas MR, Johnson DA, Johnson JA (2012) Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the alpha-synuclein mutant (A53T) mouse model. J Neurosci 32:17775–17787.  https://doi.org/10.1523/JNEUROSCI.3049-12.2012 Google Scholar
  58. 58.
    Garcia-Reitböck P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E et al (2010) SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease. Brain 133:2032–2044.  https://doi.org/10.1093/brain/awq132 Google Scholar
  59. 59.
    George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–372Google Scholar
  60. 60.
    Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI et al (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989Google Scholar
  61. 61.
    Gittis AH, Brasier DJ (2015) Astrocytes tell neurons when to listen up. Science 349:690–691.  https://doi.org/10.1126/science.aad0678 Google Scholar
  62. 62.
    Goedert M, Masuda-Suzukake M, Falcon B (2017) Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration. Brain 140:266–278.  https://doi.org/10.1093/brain/aww230 Google Scholar
  63. 63.
    Gray MT, Gray MT, Munoz DG, Gray DA, Schlossmacher MG, Woulfe JM (2014) Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects. Mov Disord 29:991–998.  https://doi.org/10.1002/mds.25779 Google Scholar
  64. 64.
    Gu X-L, Long C-X, Sun L, Xie C, Lin X, Cai H (2010) Astrocytic expression of Parkinson’s disease-related A53T alpha-synuclein causes neurodegeneration in mice. Mol Brain 3:12.  https://doi.org/10.1186/1756-6606-3-12 Google Scholar
  65. 65.
    Hasegawa T, Konno M, Baba T, Sugeno N, Kikuchi A, Kobayashi M et al (2011) The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of α-synuclein. PLoS One 6:e29460.  https://doi.org/10.1371/journal.pone.0029460 Google Scholar
  66. 66.
    Hishikawa N, Hashizume Y, Yoshida M, Sobue G (2001) Widespread occurrence of argyrophilic glial inclusions in Parkinson’s disease. Neuropathol Appl Neurobiol 27:362–372Google Scholar
  67. 67.
    Ihse E, Yamakado H, van Wijk XM, Lawrence R, Esko JD, Masliah E (2017) Cellular internalization of alpha-synuclein aggregates by cell surface heparan sulfate depends on aggregate conformation and cell type. Sci Rep 7:9008.  https://doi.org/10.1038/s41598-017-08720-5 Google Scholar
  68. 68.
    Imaizumi Y, Okada Y, Akamatsu W, Koike M, Kuzumaki N, Hayakawa H et al (2012) Mitochondrial dysfunction associated with increased oxidative stress and α-synuclein accumulation in PARK2 iPSC-derived neurons and postmortem brain tissue. Mol Brain 5:35.  https://doi.org/10.1186/1756-6606-5-35 Google Scholar
  69. 69.
    Innamorato NG, Jazwa A, Rojo AI, García C, Fernández-Ruiz J, Grochot-Przeczek A et al (2010) Different susceptibility to the Parkinson’s toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1. PLoS One 5:e11838.  https://doi.org/10.1371/journal.pone.0011838 Google Scholar
  70. 70.
    International Parkinson Disease Genomics Consortium, Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin U-M, Saad M et al (2011) Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet 377:641–649.  https://doi.org/10.1016/S0140-6736(10)62345-8 Google Scholar
  71. 71.
    Jang A, Lee H-J, Suk J-E, Jung J-W, Kim K-P, Lee S-J (2010) Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem 113:1263–1274.  https://doi.org/10.1111/j.1471-4159.2010.06695.x Google Scholar
  72. 72.
    Jazwa A, Rojo AI, Innamorato NG, Hesse M, Fernández-Ruiz J, Cuadrado A (2011) Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal 14:2347–2360.  https://doi.org/10.1089/ars.2010.3731 Google Scholar
  73. 73.
    Jellinger KA (2000) Cell death mechanisms in Parkinson’s disease. J Neural Transm 107:1–29.  https://doi.org/10.1007/s007020050001 Google Scholar
  74. 74.
    Jellinger KA (2018) Multiple system atrophy: an oligodendroglioneural synucleinopathy1. J Alzheimers Dis 62:1141–1179.  https://doi.org/10.3233/JAD-170397 Google Scholar
  75. 75.
    Jellinger KA, Lantos PL (2010) Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 119:657–667.  https://doi.org/10.1007/s00401-010-0672-3 Google Scholar
  76. 76.
    Johnson DA, Johnson JA (2015) Nrf2—a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med 88:253–267.  https://doi.org/10.1016/j.freeradbiomed.2015.07.147 Google Scholar
  77. 77.
    Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB et al (2015) Colonic bacterial composition in Parkinson’s disease. Mov Disord 30:1351–1360.  https://doi.org/10.1002/mds.26307 Google Scholar
  78. 78.
    Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942–952.  https://doi.org/10.1038/nn.4043 Google Scholar
  79. 79.
    Kim WS, Kågedal K, Halliday GM (2014) Alpha-synuclein biology in Lewy body diseases. Alzheimers Res Ther 6:73.  https://doi.org/10.1186/s13195-014-0073-2 Google Scholar
  80. 80.
    Klingelhoefer L, Reichmann H (2015) Pathogenesis of Parkinson disease—the gut-brain axis and environmental factors. Nat Rev Neurol 11:625–636.  https://doi.org/10.1038/nrneurol.2015.197 Google Scholar
  81. 81.
    Kojima W, Kujuro Y, Okatsu K, Bruno Q, Koyano F, Kimura M et al (2016) Unexpected mitochondrial matrix localization of Parkinson’s disease-related DJ-1 mutants but not wild-type DJ-1. Genes Cells 21:772–788.  https://doi.org/10.1111/gtc.12382 Google Scholar
  82. 82.
    Koller EJ, Brooks MMT, Golde TE, Giasson BI, Chakrabarty P (2017) Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice. Mol Neurodegener 12:1.  https://doi.org/10.1186/s13024-016-0142-z Google Scholar
  83. 83.
    Koob AO, Paulino AD, Masliah E (2010) GFAP reactivity, apolipoprotein E redistribution and cholesterol reduction in human astrocytes treated with alpha-synuclein. Neurosci Lett 469:11–14.  https://doi.org/10.1016/j.neulet.2009.11.034 Google Scholar
  84. 84.
    Koprich JB, Kalia LV, Brotchie JM (2017) Animal models of α-synucleinopathy for Parkinson disease drug development. Nat Rev Neurosci 18:515–529.  https://doi.org/10.1038/nrn.2017.75 Google Scholar
  85. 85.
    Kosel S, Egensperger R, von Eitzen U, Mehraein P, Graeber MB (1997) On the question of apoptosis in the parkinsonian substantia nigra. Acta Neuropathol 93:105–108Google Scholar
  86. 86.
    Kovacs GG, Lee VM, Trojanowski JQ (2017) Protein astrogliopathies in human neurodegenerative diseases and aging. Brain Pathol 27:675–690.  https://doi.org/10.1111/bpa.12536 Google Scholar
  87. 87.
    Kovacs GG, Wagner U, Dumont B, Pikkarainen M, Osman AA, Streichenberger N et al (2012) An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology. Acta Neuropathol 124:37–50.  https://doi.org/10.1007/s00401-012-0964-x Google Scholar
  88. 88.
    Kramer ML, Schulz-Schaeffer WJ (2007) Presynaptic α-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci 27:1405–1410.  https://doi.org/10.1523/JNEUROSCI.4564-06.2007 Google Scholar
  89. 89.
    Lashuel HA, Overk CR, Oueslati A, Masliah E (2013) The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14:38–48.  https://doi.org/10.1038/nrn3406 Google Scholar
  90. 90.
    Lastres-Becker I, Ulusoy A, Innamorato NG, Sahin G, Rábano A, Kirik D et al (2012) α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson’s disease. Hum Mol Genet 21:3173–3192.  https://doi.org/10.1093/hmg/dds143 Google Scholar
  91. 91.
    Latge C, Cabral KMS, de Oliveira GAP, Raymundo DP, Freitas JA, Johanson L et al (2015) The solution structure and dynamics of full-length human cerebral dopamine neurotrophic factor and its neuroprotective role against α-synuclein oligomers. J Biol Chem 290:20527–20540.  https://doi.org/10.1074/jbc.M115.662254 Google Scholar
  92. 92.
    Le W-D, Xu P, Jankovic J, Jiang H, Appel SH, Smith RG et al (2003) Mutations in NR4A2 associated with familial Parkinson disease. Nat Genet 33:85–89.  https://doi.org/10.1038/ng1066 Google Scholar
  93. 93.
    Lee H-J, Suk J-E, Patrick C, Bae E-J, Cho J-H, Rho S et al (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285:9262–9272.  https://doi.org/10.1074/jbc.M109.081125 Google Scholar
  94. 94.
    Li W, West N, Colla E, Pletnikova O, Troncoso JC, Marsh L et al (2005) Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc Natl Acad Sci USA 102:2162–2167.  https://doi.org/10.1073/pnas.0406976102 Google Scholar
  95. 95.
    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487.  https://doi.org/10.1038/nature21029 Google Scholar
  96. 96.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795.  https://doi.org/10.1038/nature05292 Google Scholar
  97. 97.
    Lindstrom V, Gustafsson G, Sanders LH, Howlett EH, Sigvardson J, Kasrayan A et al (2017) Extensive uptake of alpha-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Mol Cell Neurosci 45:54.  https://doi.org/10.1016/j.mcn.2017.04.009 Google Scholar
  98. 98.
    Loria F, Vargas JY, Bousset L, Syan S, Salles A, Melki R et al (2017) α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 134:789–808.  https://doi.org/10.1007/s00401-017-1746-2 Google Scholar
  99. 99.
    Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VMY (2012) Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 209:975–986.  https://doi.org/10.1084/jem.20112457 Google Scholar
  100. 100.
    Mao X, Ou MT, Karuppagounder SS, Kam T-I, Yin X, Xiong Y et al (2016) Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353:3374.  https://doi.org/10.1126/science.aah3374 Google Scholar
  101. 101.
    Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815Google Scholar
  102. 102.
    McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291Google Scholar
  103. 103.
    Melki R (2015) Role of different alpha-synuclein strains in synucleinopathies, similarities with other neurodegenerative diseases. J Parkinsons Dis 5:217–227.  https://doi.org/10.3233/JPD-150543 Google Scholar
  104. 104.
    Mendritzki S, Schmidt S, Sczepan T, Zhu X-R, Segelcke D, Lübbert H (2010) Spinal cord pathology in alpha-synuclein transgenic mice. Parkinsons Dis 2010:1–9.  https://doi.org/10.4061/2010/375462 Google Scholar
  105. 105.
    Miyazaki I, Asanuma M (2008) Dopaminergic neuron-specific oxidative stress caused by dopamine itself. Acta Med Okayama 62:141–150Google Scholar
  106. 106.
    Mochizuki H, Goto K, Mori H, Mizuno Y (1996) Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 137:120–123Google Scholar
  107. 107.
    Molofsky AV, Deneen B (2015) Astrocyte development: a guide for the perplexed. Glia 63:1320–1329.  https://doi.org/10.1002/glia.22836 Google Scholar
  108. 108.
    Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K (2002) Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp Neurol 176:98–104Google Scholar
  109. 109.
    Murray IVJ, Giasson BI, Quinn SM, Koppaka V, Axelsen PH, Ischiropoulos H et al (2003) Role of α-synuclein carboxy-terminus on fibril formation in vitro . Biochemistry 42:8530–8540.  https://doi.org/10.1021/bi027363r Google Scholar
  110. 110.
    Nakamura K, Mori F, Kon T, Tanji K, Miki Y, Tomiyama M et al (2016) Accumulation of phosphorylated α-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration. Neuropathology 36:157–167.  https://doi.org/10.1111/neup.12243 Google Scholar
  111. 111.
    Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K et al (2011) Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem 286:20710–20726.  https://doi.org/10.1074/jbc.M110.213538 Google Scholar
  112. 112.
    Ngolab J, Trinh I, Rockenstein E, Mante M, Florio J, Trejo M et al (2017) Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology. Acta Neuropathol Commun 5:46.  https://doi.org/10.1186/s40478-017-0445-5 Google Scholar
  113. 113.
    Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P et al (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8:267–280.  https://doi.org/10.1016/j.stem.2011.01.013 Google Scholar
  114. 114.
    Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK et al (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767Google Scholar
  115. 115.
    Ouberai MM, Wang J, Swann MJ, Galvagnion C, Guilliams T, Dobson CM et al (2013) α-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling. J Biol Chem 288:20883–20895.  https://doi.org/10.1074/jbc.M113.478297 Google Scholar
  116. 116.
    Outeiro TF, Lindquist S (2003) Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 302:1772–1775.  https://doi.org/10.1126/science.1090439 Google Scholar
  117. 117.
    Paillusson S, Clairembault T, Biraud M, Neunlist M, Derkinderen P (2013) Activity-dependent secretion of alpha-synuclein by enteric neurons. J Neurochem 125:512–517.  https://doi.org/10.1111/jnc.12131 Google Scholar
  118. 118.
    Peelaerts W, Bousset L, Baekelandt V, Melki R (2018) ɑ-Synuclein strains and seeding in Parkinson’s disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences. Cell Tissue Res 373:195–212.  https://doi.org/10.1007/s00441-018-2839-5 Google Scholar
  119. 119.
    Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M et al (2015) α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344.  https://doi.org/10.1038/nature14547 Google Scholar
  120. 120.
    Pekny M, Pekna M, Messing A, Steinhauser C, Lee J-M, Parpura V et al (2016) Astrocytes: a central element in neurological diseases. Acta Neuropathol 131:323–345.  https://doi.org/10.1007/s00401-015-1513-1 Google Scholar
  121. 121.
    Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A, Robinson JL et al (2018) Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies. Nature 557:558–563.  https://doi.org/10.1038/s41586-018-0104-4 Google Scholar
  122. 122.
    Peng C, Gathagan RJ, Lee VM-Y (2018) Distinct α-synuclein strains and implications for heterogeneity among α-synucleinopathies. Neurobiol Dis 109:209–218.  https://doi.org/10.1016/j.nbd.2017.07.018 Google Scholar
  123. 123.
    Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431.  https://doi.org/10.1016/j.tins.2009.05.001 Google Scholar
  124. 124.
    Piao Y-S, Mori F, Hayashi S, Tanji K, Yoshimoto M, Kakita A et al (2003) Alpha-synuclein pathology affecting Bergmann glia of the cerebellum in patients with alpha-synucleinopathies. Acta Neuropathol 105:403–409.  https://doi.org/10.1007/s00401-002-0655-0 Google Scholar
  125. 125.
    Pieri L, Chafey P, Le Gall M, Clary G, Melki R, Redeker V (2016) Cellular response of human neuroblastoma cells to α-synuclein fibrils, the main constituent of Lewy bodies. Biochim Biophys Acta 1860:8–19.  https://doi.org/10.1016/j.bbagen.2015.10.007 Google Scholar
  126. 126.
    Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J et al (2017) Parkinson disease. Nat Rev Dis Prim 3:17013.  https://doi.org/10.1038/nrdp.2017.13 Google Scholar
  127. 127.
    Rannikko EH, Weber SS, Kahle PJ (2015) Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes. BMC Neurosci 16:57.  https://doi.org/10.1186/s12868-015-0192-0 Google Scholar
  128. 128.
    Ravenholt RT, Foege WH (1982) 1918 influenza, encephalitis lethargica, parkinsonism. Lancet (Lond, Engl) 2:860–864Google Scholar
  129. 129.
    Rekas A, Ahn KJ, Kim J, Carver JA (2012) The chaperone activity of α-synuclein: utilizing deletion mutants to map its interaction with target proteins. Proteins 80:1316–1325.  https://doi.org/10.1002/prot.24028 Google Scholar
  130. 130.
    Rostami J, Holmqvist S, Lindström V, Sigvardson J, Westermark GT, Ingelsson M et al (2017) Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes. J Neurosci 37:11835–11853.  https://doi.org/10.1523/JNEUROSCI.0983-17.2017 Google Scholar
  131. 131.
    Sacino AN, Brooks M, McKinney AB, Thomas MA, Shaw G, Golde TE, Giasson BI (2014) Brain injection of alpha-synuclein induces multiple proteinopathies, gliosis, and a neuronal injury marker. J Neurosci 34:12368–12378.  https://doi.org/10.1523/JNEUROSCI.2102-14.2014 Google Scholar
  132. 132.
    Sacino AN, Brooks M, Thomas MA, McKinney AB, Lee S, Regenhardt RW et al (2014) Intramuscular injection of -synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci 111:10732–10737.  https://doi.org/10.1073/pnas.1321785111 Google Scholar
  133. 133.
    Sacino AN, Thomas MA, Ceballos-Diaz C, Cruz PE, Rosario AM et al (2013) Conformational templating of α-synuclein aggregates in neuronal-glial cultures. Mol Neurodegener 8:17.  https://doi.org/10.1186/1750-1326-8-17 Google Scholar
  134. 134.
    Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG et al (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59.  https://doi.org/10.1016/j.cell.2009.01.038 Google Scholar
  135. 135.
    Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE et al (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167:1469–1480.  https://doi.org/10.1016/j.cell.2016.11.018 Google Scholar
  136. 136.
    Sarafian TA, Littlejohn K, Yuan S, Fernandez C, Cilluffo M, Koo B-K et al (2017) Stimulation of synaptoneurosome glutamate release by monomeric and fibrillated α-synuclein. J Neurosci Res 95:1871–1887.  https://doi.org/10.1002/jnr.24024 Google Scholar
  137. 137.
    Sato H, Kato T, Arawaka S (2013) The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson’s disease: a review of in vivo models. Rev Neurosci 24:115–123.  https://doi.org/10.1515/revneuro-2012-0071 Google Scholar
  138. 138.
    Scheperjans F, Aho V, Pereira PAB, Koskinen K, Paulin L, Pekkonen E et al (2015) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 30:350–358.  https://doi.org/10.1002/mds.26069 Google Scholar
  139. 139.
    Scholz SW, Houlden H, Schulte C, Sharma M, Li A, Berg D et al (2009) SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 65:610–614.  https://doi.org/10.1002/ana.21685 Google Scholar
  140. 140.
    Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A (2004) DJ-1 is a redox-dependent molecular chaperone that inhibits α-synuclein aggregate formation. PLoS Biol 2:e362.  https://doi.org/10.1371/journal.pbio.0020362 Google Scholar
  141. 141.
    Shoji M, Harigaya Y, Sasaki A, Uéda K, Ishiguro K, Matsubara E et al (2000) Accumulation of NACP/alpha-synuclein in Lewy body disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 68:605–608Google Scholar
  142. 142.
    Shrivastava AN, Redeker V, Fritz N, Pieri L, Almeida LG, Spolidoro M et al (2015) Synuclein assemblies sequester neuronal 3-Na +/K + -ATPase and impair Na + gradient. EMBO J 34:2408–2423.  https://doi.org/10.15252/embj.201591397 Google Scholar
  143. 143.
    Shrivastava AN, Redeker V, Fritz N, Pieri L, Almeida LG, Spolidoro M et al (2016) Data in support of the identification of neuronal and astrocyte proteins interacting with extracellularly applied oligomeric and fibrillar alpha-synuclein assemblies by mass spectrometry. Data Br 7:221–228.  https://doi.org/10.1016/j.dib.2016.02.018 Google Scholar
  144. 144.
    Song J-J, Oh S-M, Kwon O-C, Wulansari N, Lee H-S, Chang M-Y et al (2017) Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model. J Clin Investig 128:463–482.  https://doi.org/10.1172/JCI93924 Google Scholar
  145. 145.
    Song YJC, Halliday GM, Holton JL, Lashley T, O’Sullivan SS, McCann H et al (2009) Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol 68:1073–1083.  https://doi.org/10.1097/NEN.0b013e3181b66f1b Google Scholar
  146. 146.
    Sorrentino ZA, Brooks MMT, Hudson V, Rutherford NJ, Golde TE, Giasson BI et al (2017) Intrastriatal injection of α-synuclein can lead to widespread synucleinopathy independent of neuroanatomic connectivity. Mol Neurodegener 12:40.  https://doi.org/10.1186/s13024-017-0182-z Google Scholar
  147. 147.
    Sorrentino ZA, Vijayaraghavan N, Gorion K-M, Riffe CJ, Strang KH, Caldwell J et al (2018) Physiological carboxy-truncation of α-synuclein potentiates the prion-like formation of pathological inclusions. J Biol Chem.  https://doi.org/10.1074/jbc.ra118.005603 Google Scholar
  148. 148.
    Sorrentino ZA, Xia Y, Funk C, Riffe CJ, Rutherford NJ, Ceballos Diaz C et al (2018) Motor neuron loss and neuroinflammation in a model of α-synuclein-induced neurodegeneration. Neurobiol Dis 120:98–106.  https://doi.org/10.1016/j.nbd.2018.09.005 Google Scholar
  149. 149.
    Stefanova N, Klimaschewski L, Poewe W, Wenning GK, Reindl M (2001) Glial cell death induced by overexpression of alpha-synuclein. J Neurosci Res 65:432–438.  https://doi.org/10.1002/jnr.1171 Google Scholar
  150. 150.
    Sullivan A, O′Keeffe G (2016) Neurotrophic factor therapy for Parkinson′s disease: past, present and future. Neural Regen Res 11:205.  https://doi.org/10.4103/1673-5374.177710 Google Scholar
  151. 151.
    Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J et al (2017) T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546:656–661.  https://doi.org/10.1038/nature22815 Google Scholar
  152. 152.
    Sung JY, Park SM, Lee C-H, Um JW, Lee HJ, Kim J et al (2005) Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases. J Biol Chem 280:25216–25224.  https://doi.org/10.1074/jbc.M503341200 Google Scholar
  153. 153.
    Surendranathan A, Su L, Mak E, Passamonti L, Hong YT, Arnold R et al (2018) Early microglial activation and peripheral inflammation in dementia with Lewy bodies. Brain 141:3415–3427.  https://doi.org/10.1093/brain/awy265 Google Scholar
  154. 154.
    Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18:101–113.  https://doi.org/10.1038/nrn.2016.178 Google Scholar
  155. 155.
    Taipa R, Pereira C, Reis I, Alonso I, Bastos-Lima A, Melo-Pires M et al (2016) DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain 139:1680–1687.  https://doi.org/10.1093/brain/aww080 Google Scholar
  156. 156.
    Takeda A, Hashimoto M, Mallory M, Sundsumo M, Hansen L, Masliah E (2000) C-terminal alpha-synuclein immunoreactivity in structures other than Lewy bodies in neurodegenerative disorders. Acta Neuropathol 99:296–304Google Scholar
  157. 157.
    Takeda H, Inazu M, Matsumiya T (2002) Astroglial dopamine transport is mediated by norepinephrine transporter. Naunyn Schmiedebergs Arch Pharmacol 366:620–623.  https://doi.org/10.1007/s00210-002-0640-0 Google Scholar
  158. 158.
    Tanji K, Imaizumi T, Yoshida H, Mori F, Yoshimoto M, Satoh K et al (2001) Expression of alpha-synuclein in a human glioma cell line and its up-regulation by interleukin-1beta. NeuroReport 12:1909–1912Google Scholar
  159. 159.
    Terada S, Ishizu H, Haraguchi T, Takehisa Y, Tanabe Y, Kawai K et al (2000) Tau-negative astrocytic star-like inclusions and coiled bodies in dementia with Lewy bodies. Acta Neuropathol 100:464–468Google Scholar
  160. 160.
    Terada S, Ishizu H, Yokota O, Tsuchiya K, Nakashima H, Ishihara T et al (2003) Glial involvement in diffuse Lewy body disease. Acta Neuropathol 105:163–169.  https://doi.org/10.1007/s00401-002-0622-9 Google Scholar
  161. 161.
    Theillet F-X, Binolfi A, Bekei B, Martorana A, Rose HM, Stuiver M et al (2016) Structural disorder of monomeric α-synuclein persists in mammalian cells. Nature 530:45–50.  https://doi.org/10.1038/nature16531 Google Scholar
  162. 162.
    Togo T, Iseki E, Marui W, Akiyama H, Uéda K, Kosaka K (2001) Glial involvement in the degeneration process of Lewy body-bearing neurons and the degradation process of Lewy bodies in brains of dementia with Lewy bodies. J Neurol Sci 184:71–75Google Scholar
  163. 163.
    Tong J, Ang L-C, Williams B, Furukawa Y, Fitzmaurice P, Guttman M et al (2015) Low levels of astroglial markers in Parkinson’s disease: relationship to alpha-synuclein accumulation. Neurobiol Dis 82:243–253.  https://doi.org/10.1016/j.nbd.2015.06.010 Google Scholar
  164. 164.
    Tong J, Wong H, Guttman M, Ang LC, Forno LS, Shimadzu M et al (2010) Brain alpha-synuclein accumulation in multiple system atrophy, Parkinson’s disease and progressive supranuclear palsy: a comparative investigation. Brain 133:172–188.  https://doi.org/10.1093/brain/awp282 Google Scholar
  165. 165.
    Uchihara T, Giasson BI (2016) Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131:49–73.  https://doi.org/10.1007/s00401-015-1485-1 Google Scholar
  166. 166.
    Vasile F, Dossi E, Rouach N (2017) Human astrocytes: structure and functions in the healthy brain. Brain Struct Funct.  https://doi.org/10.1007/s00429-017-1383-5 Google Scholar
  167. 167.
    Victoria GS, Zurzolo C (2017) The spread of prion-like proteins by lysosomes and tunneling nanotubes: implications for neurodegenerative diseases. J Cell Biol 216:2633–2644.  https://doi.org/10.1083/jcb.201701047 Google Scholar
  168. 168.
    Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20Google Scholar
  169. 169.
    Wakabayashi K, Takahashi H (1996) Gallyas-positive, tau-negative glial inclusions in Parkinson’s disease midbrain. Neurosci Lett 217:133–136Google Scholar
  170. 170.
    Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F (1988) Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol 76:217–221Google Scholar
  171. 171.
    Williamson TP, Johnson DA, Johnson JA (2012) Activation of the Nrf2-ARE pathway by siRNA knockdown of Keap1 reduces oxidative stress and provides partial protection from MPTP-mediated neurotoxicity. Neurotoxicology 33:272–279.  https://doi.org/10.1016/j.neuro.2012.01.015 Google Scholar
  172. 172.
    Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ (2003) Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science 302:1769–1772.  https://doi.org/10.1126/science.1090389 Google Scholar
  173. 173.
    Winner BM, Zhang H, Farthing MM, Karchalla LM, Lookingland KJ, Goudreau JL (2017) Metabolism of dopamine in nucleus accumbens astrocytes is preserved in aged mice exposed to MPTP. Front Aging Neurosci 9:410.  https://doi.org/10.3389/fnagi.2017.00410 Google Scholar
  174. 174.
    Woodard CM, Campos BA, Kuo S-H, Nirenberg MJ, Nestor MW, Zimmer M et al (2014) iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson’s disease. Cell Rep 9:1173–1182.  https://doi.org/10.1016/j.celrep.2014.10.023 Google Scholar
  175. 175.
    Yang YX, Latchman DS (2008) Nurr1 transcriptionally regulates the expression of α-synuclein. NeuroReport 19:867–871.  https://doi.org/10.1097/WNR.0b013e3282ffda48 Google Scholar
  176. 176.
    Yeh T-H, Lee DY, Gianino SM, Gutmann DH (2009) Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 (NF1)-regulated glial proliferation. Glia 57:1239–1249.  https://doi.org/10.1002/glia.20845 Google Scholar
  177. 177.
    Yokota O, Terada S, Ishizu H, Tsuchiya K, Kitamura Y, Ikeda K et al (2002) NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC). Acta Neuropathol 104:333–341.  https://doi.org/10.1007/s00401-002-0545-5 Google Scholar
  178. 178.
    Yun SP, Kam T-I, Panicker N, Kim S, Oh Y, Park J-S et al (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 24:931–938.  https://doi.org/10.1038/s41591-018-0051-5 Google Scholar
  179. 179.
    Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542.  https://doi.org/10.1096/fj.04-2751com Google Scholar
  180. 180.
    Zhang Z, Shen Y, Luo H, Zhang F, Peng D, Jing L et al (2018) MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson’s disease model in C. elegans by regulating ER stress and autophagy pathways. Exp Neurol 308:59–71.  https://doi.org/10.1016/j.expneurol.2018.06.016 Google Scholar
  181. 181.
    Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR (2011) Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem 286:14941–14951.  https://doi.org/10.1074/jbc.M110.211029 Google Scholar
  182. 182.
    Zhu D, Tan KS, Zhang X, Sun AY, Sun GY, Lee JC-M (2005) Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes. J Cell Sci 118:3695–3703.  https://doi.org/10.1242/jcs.02507 Google Scholar
  183. 183.
    Zondler L, Miller-Fleming L, Repici M, Gonçalves S, Tenreiro S, Rosado-Ramos R et al (2014) DJ-1 interactions with α-synuclein attenuate aggregation and cellular toxicity in models of Parkinson’s disease. Cell Death Dis 5:e1350.  https://doi.org/10.1038/cddis.2014.307 Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neuroscience, Center for Translational Research in Neurodegenerative Diseases and McKnight Brain InstituteUniversity of FloridaGainesvilleUSA

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