Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

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

References

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 1:49–59

    PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 259:83–86

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 202:17–20

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 24:197–211

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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 146:139–149

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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 3:663–666

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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 15:361–372

    Article  CAS  PubMed  Google Scholar 

  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 290:985–989

    Article  CAS  PubMed  Google Scholar 

  61. Gittis AH, Brasier DJ (2015) Astrocytes tell neurons when to listen up. Science 349:690–691. https://doi.org/10.1126/science.aad0678

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hishikawa N, Hashizume Y, Yoshida M, Sobue G (2001) Widespread occurrence of argyrophilic glial inclusions in Parkinson’s disease. Neuropathol Appl Neurobiol 27:362–372

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  73. Jellinger KA (2000) Cell death mechanisms in Parkinson’s disease. J Neural Transm 107:1–29. https://doi.org/10.1007/s007020050001

    Article  CAS  PubMed  Google Scholar 

  74. Jellinger KA (2018) Multiple system atrophy: an oligodendroglioneural synucleinopathy1. J Alzheimers Dis 62:1141–1179. https://doi.org/10.3233/JAD-170397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 93:105–108

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795. https://doi.org/10.1038/nature05292

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  101. Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 38:1285–1291

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  Google Scholar 

  105. Miyazaki I, Asanuma M (2008) Dopaminergic neuron-specific oxidative stress caused by dopamine itself. Acta Med Okayama 62:141–150

    CAS  PubMed  Google Scholar 

  106. Mochizuki H, Goto K, Mori H, Mizuno Y (1996) Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 137:120–123

    Article  CAS  PubMed  Google Scholar 

  107. Molofsky AV, Deneen B (2015) Astrocyte development: a guide for the perplexed. Glia 63:1320–1329. https://doi.org/10.1002/glia.22836

    Article  PubMed  Google Scholar 

  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 176:98–104

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 60:759–767

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ravenholt RT, Foege WH (1982) 1918 influenza, encephalitis lethargica, parkinsonism. Lancet (Lond, Engl) 2:860–864

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 68:605–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 99:296–304

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 12:1909–1912

    Article  CAS  PubMed  Google Scholar 

  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 100:464–468

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 184:71–75

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 99:14–20

    Article  CAS  PubMed  Google Scholar 

  169. Wakabayashi K, Takahashi H (1996) Gallyas-positive, tau-negative glial inclusions in Parkinson’s disease midbrain. Neurosci Lett 217:133–136

    Article  CAS  PubMed  Google Scholar 

  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 76:217–221

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Center for Translational Research in Neurodegenerative Diseases and McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA

    Zachary A. Sorrentino, Benoit I. Giasson & Paramita Chakrabarty

Authors
  1. Zachary A. Sorrentino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benoit I. Giasson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paramita Chakrabarty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paramita Chakrabarty.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sorrentino, Z.A., Giasson, B.I. & Chakrabarty, P. α-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease. Acta Neuropathol 138, 1–21 (2019). https://doi.org/10.1007/s00401-019-01977-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-019-01977-2

Keywords

Search

Navigation