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Open Access 01-12-2014 | Review

Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease

Authors: Christopher A Bates, Wei Zheng

Published in: Fluids and Barriers of the CNS | Issue 1/2014

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the accumulation of α-Synuclein (a-Syn) into Lewy body inclusions and the loss of dopaminergic neurons in the substantia nigra (SN). Accumulation of a-Syn can induce a progressive, cyclical pathology that results in the transmission of toxic, aggregated a-Syn species to healthy neurons, leading to further neurodegeneration such as occurs in PD. The blood–brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers (BCSFB) are responsible for regulating the access of nutrients and other molecules to the brain, but very little is known about their regulatory roles in maintaining the homeostasis of a-Syn in the CSF and brain parenchyma. This review analyzes the current literature reports on the transport of a-Syn by various brain cell types with a particular focus on the potential transport mechanisms of a-Syn at the BBB and BCSFB. The indication of altered a-Syn transport by brain barriers in PD pathoetiology and the perspectives in this research area are also discussed.

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Kamel F: Paths from pesticides to Parkinson’s. Science. 2013, 341: 722-723.CrossRefPubMed

Auluck P, Caraveo G, Lindquist S: α-synuclein: membrane interactions and toxicity in Parkinson's disease. Ann Rev Cell Dev Biol. 2013, 26: 211-233.CrossRef

Braak H, Bohl JR, Müller CM, Rüb U, de Vos RAI, Del Tredici K: Stanley Fahn lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Movement Dis. 2006, 21: 2042-2051.CrossRefPubMed

Duda JE, Lee VMY, Trojanowski JQ: Neuropathy of synuclein aggregates: new insights into mechanisms of neurodegenerative diseases. J Neurosci Res. 2000, 61: 121-127.CrossRefPubMed

Murphy D, Rueter SM, Trojanowski JQ, Lee VMY: Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000, 20: 3214-3220.PubMed

Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ: A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci. 2002, 22: 3090-3099.PubMed

Clayton DF, George JM: Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res. 1999, 58: 120-129.CrossRefPubMed

Ellis CE, Murphy EJ, Mitchell DC, Golovko MY, Scaglia F, Barceló-Coblijn GC, Nussbaum RL: Mitochondrial lipid abnormality and electron transport chain impairment in mice lacking α-synuclein. Mol Cell Bio. 2005, 25: 10190-10201.CrossRef

Winklhofer KF, Haass C: Mitochondrial dysfunction in Parkinson’s disease. Biochem Biophys Acta. 1802, 2010: 29-44.

10.

Kalia LV, Kalia SK, McLean PJ, Lozano AM, Lang AE: α-synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol. 2013, 73: 155-169.PubMedCentralCrossRefPubMed

11.

Bodner CR, Maltsev AS, Dobson CM, Bax A: Differential phospholipid binding of α-synuclein variants implicated in Parkinson’s disease revealed by solution NMR spectroscopy. Biogeosciences. 2010, 49: 862-871.

12.

Kirik D, Rosenblad C, Burger C, Lundberg C, Johanson TE, Muzyczka N, Mandel RJ, Björklund A: Parkinson-like neurodegeneration induced by targeted overexpression of α-synuclein in the nigrostriatal system. J Neurosci. 2002, 22: 2780-2791.PubMed

13.

Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Bjòrklund A: Nigrostriatal a-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: a new primate model of Parkinson’s disease. PNAS. 2003, 100: 2884-2889.PubMedCentralCrossRefPubMed

14.

Gombash SE, Manfredsson FP, Kemp CJ, Kuhn NC, Fleming SM, Egan AE, Grant LM, Ciucci MR, MacKeigan JP, Sortwell CE: Morphological and behavioral impact of AAV2/5-mediated overexpression of human wildtype alpha-synuclein in the rat nigrostriatal system. PLoS ONE. 2013, 8: 1-15.CrossRef

15.

Lee H, Patel S, Lee S: Intravesicular localization and exocytosis of α-synuclein and its aggregates. J Neurosci. 2005, 25: 6016-6024.CrossRefPubMed

16.

Lee H, Khoshaghideh F, Patel S, Lee S: Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J Neurosci. 2004, 24: 1888-1896.CrossRefPubMed

17.

Lee H, Cho E, Lee KW, Kim J, Cho S, Lee S: Autophagic failure promotes the exocytosis and intracellular transfer of α-synuclein. Exp Mol Med. 2013, 45: 1-9.CrossRef

18.

Brown PD, Davies SL, Speake T, Millar ID: Molecular mechanisms of cerebrospinal fluid production. Neurosci. 2004, 129: 957-970.CrossRef

19.

Smith DE, Johanson CE, Keep RF: Peptide and peptide analog transport systems at the blood-CSF barrier. Adv Drug Del Rev. 2004, 56: 1765-1791.CrossRef

20.

McCaffrey G, Davis TP: Physiology and pathophysiology of the blood–brain barrier p-glycoprotein and occludin trafficking as therapeutic targets to optimize central nervous system drug delivery. J Investig Med. 2012, 60: 1131-1140.PubMed

21.

Sobue K, Yamamoto N, Yoneda K, Hodgson ME, Yamashiro K, Tsuruoka N, Tsuda T, Katsuya H, Miura Y, Asai K, Kato T: Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci Res. 1999, 35: 155-164.CrossRefPubMed

22.

Abbott NJ, Rönnbäck L, Hansson E: Astrocyte-endothelial interactions at the blood–brain barrier. Nature Rev. 2006, 7: 41-53.CrossRef

23.

Kim KS: Mechanisms of microbial traversal of the blood–brain barrier. Nature Rev. 2008, 6: 625-626.

24.

Bernacki J, Dobrowolska A, Nierwińska K, Małecki A: Physiology and pharmacological role of the blood–brain barrier. Pharmacol Rep. 2008, 2008 (60): 600-622.

25.

Zheng W, Aschner M, Ghersi-Egea J: Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol. 2003, 192: 1-11.PubMedCentralCrossRefPubMed

26.

Johanson CE, Duncan JA, Stopa EG, Baird A: Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharma Res. 2005, 22: 1011-1037.CrossRef

27.

Spector R, Johanson CE: Sustained choroid plexus function in human elderly and Alzheimer’s disease patients. Fluids Barriers CNS. 2013, 10: 28-PubMedCentralCrossRefPubMed

28.

Desplats P, Lee H, Bae E, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee S: Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. PNAS. 2009, 106: 13010-13015.PubMedCentralCrossRefPubMed

29.

Angot E, Steiner JA, Lema Tomé CM, Ekström P, Mattson B, Björklund A, Brundin P: Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS ONE. 2012, 7: 1-11.CrossRef

30.

Lee H, Suk J, Bae E, Lee J, Paik SR, Lee S: Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int’l J Biochem Cell Bio. 2008, 40: 1835-1849.CrossRef

31.

Freeman D, Cedilos R, Choyke S, Lukic Z, McGuire K, Marvin S, Burrage AM, Sudholt S, Rana A, O’Connor C, Wiethoff CM, Campbell EM: Alpha-synuclein induces lysosomal rupture and cathespin-dependent reactive oxidative species following endocytosis. PLoS ONE. 2013, 8: e62143-PubMedCentralCrossRefPubMed

32.

Büchel F, Saliger S, Dräger A, Hoffman S, Wrzodek C, Zell A, Kahle PJ: Parkinson’s disease: dopaminergic neuronal model is consistent with experimental finding of increased extracellular transport of α-synuclein. BMC Neurosci. 2013, 14: 1-12.CrossRef

33.

Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H: NACP/α-synuclein-positive filamentous inclusions in astrocytes, and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol. 2000, 99: 14-20.CrossRefPubMed

34.

Braak H, Sastre M, Del Tredici K: Development of α-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson’s disease. Acta Neuropathol. 2007, 114: 231-241.CrossRefPubMed

35.

Lee H, Kim C, Lee S: Alpha-synuclein stimulation of astrocytes: potential role for neuroinflammation and neuroprotection. Oxid Med Cell Longev. 2010, 3: 283-287.PubMedCentralCrossRefPubMed

36.

Lee H, Suk J, Patrick C, Bae E, Cho J, Rho S, Hwang D, Masliah E, Lee S: Direct transfer of a-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010, 285: 2962-9272.

37.

Kim JN, Kim MK, Cho KS, Choi CS, Park SH, Yang S, Joo SH, Park JH, Bahn G, Shin CY, Lee H, Han S, Kwon KJ: Valproic acid regulates α-synuclein expression through JNK pathway in rat primary astrocytes. Biomol Ther. 2013, 21: 222-228.CrossRef

38.

Tamo W, Imaizumi T, Tanji K, Yoshi H, Mori F, Yoshimoto M, Takahashi H, Fukuda I, Wakabayashi K, Satoh K: Expression of α-synuclein, the precursor of non-amyloid β component of Alzheimer’s disease amyloid, in human cerebral blood vessels. Neurosci Lett. 2002, 326: 5-8.CrossRefPubMed

39.

Mollenhauer B, Trautmann E, Otte B, Ng J, Spreer A, Lange P, Sixel-Döring F, Hakimi M, VonSattel J, Nussbaum R, Trenkwalder C, Schlossmacher MG: α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system. J Neural Transm. 2012, 119: 739-746.PubMedCentralCrossRefPubMed

40.

Foulds PG, Diggle P, Mitchell JD, Parker A, Hasegawa M, Masuda-Suzukake M, Mann DMA, Allsop D: A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson’s disease. Sci Rep. 2013, 3: 2540-PubMedCentralCrossRefPubMed

41.

Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, Montine TJ, Hancock AM, Hwang H, Pan C, Bradner J, Kang UJ, Jensen PH, Zhang J: DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain. 2010, 133: 713-726.PubMedCentralCrossRefPubMed

42.

Mollenhauer B, Trautmann E, Taylor P, Manniger P, Sixel-Döring F, Ebentheuer J, Trenkwalder C, Schlossmacher MG: Total CSF α-synuclein is lower in de novo Parkinson patients than in healthy subjects. J Neurosci Lett. 2013, 532: 44-48.CrossRef

43.

Walker SJ, Grant KA: Peripheral blood α-synuclein mRNA levels are elevated in cynomolgus monkeys that chronically self-administer ethanol. Alcohol. 2006, 38: 1-4.CrossRefPubMed

44.

Fauvet B, Kamdem MM, Fares MB, Desobry C, Michael S, Ardah MT, Tsika E, Coune P, Prudent M, Lion N, Eliezer D, Moore DJ, Schneider B, Aebischer P, El-Agnaf OM, Masliah E, Lashuel HA: Alpha-Synuclein in the central nervous system and from erythrocytes, mammalian cells and E. coli exists predominantly as a disordered monomer. J Biol Chem. 2012, 287: 15345-15364.PubMedCentralCrossRefPubMed

45.

Grathwohl SA, Steiner JA, Britschgi M, Brundin P: Mind the gut: secretion of α-synuclein by enteric neurons. J Neurochem. 2013, 125: 487-490.CrossRefPubMed

46.

Bates CA, Zheng G, Fu X, Zheng W: Expression and aggregation of α-synuclein in the blood-CSF barrier: Initial evidence for the influence of cellular manganese and copper status [abstract]. Toxicologist. 2013, 132: 1862-

47.

Zheng W, Zhao Q: Establishment and characterization of an immortalized Z310 choroidal epithelial cell line from murine choroid plexus. Brain Res. 2002, 958: 371-380.PubMedCentralCrossRefPubMed

48.

McMahon HT, Boucrot E: Molecular mechanism and physiological functions of clathrin-mediated endocytosis. Nature Rev Mol Biol. 2011, 12: 517-533.CrossRef

49.

Bates CA, Fu X, Ysselstein D, Rochet J, Zheng W: Transport of α-synuclein at the blood-cerebrospinal fluid barrier and effects of heavy metal toxicities: potential role in Parkinson’s disease pathoetiology [abstract]. Toxicologist. 2014, 138: 1349-

50.

André C, Truong TT, Robert JF, Guillaume YC: Effect of metals on herbicides-α-synuclein association: a possible factor in neurodegenerative disease studied by capillary electrophoresis. Electrophoresis. 2005, 26: 3256-3264.CrossRefPubMed

51.

Santner A, Uversky VN: Metalloproteomics and metal toxicology of α-synuclein. Metallomics. 2010, 2: 378-392.CrossRefPubMed

52.

Cookson MR, Hardy J, Lewis PA: Genetic neuropathology of Parkinson’s disease. Int J Clin Exp Pathol. 2008, 1: 217-231.PubMedCentralPubMed

53.

Covy JP, Giasson BI: α-synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of Parkinson’s disease. Neurotox. 2011, 32: 622-629.CrossRef

54.

Yue Z, Yang XW: Dangerous duet: LRRK2 and α-synuclein jam at CMA. Nat Neurosci. 2013, 16: 375-377.CrossRefPubMed

55.

Kisos H, Puka K, Ben-Hur T, Richter-Landsberg C, Sharon R: Increased neuronal α-synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling α-synucleinopathies. PLoS ONE. 2012, 7: e46817-PubMedCentralCrossRefPubMed

56.

Lee H, Suk J, Bae E, Lee S: Clearance and deposition of extracellular α-synuclein aggregates in microglia. Biochem Biophys Res Comm. 2008, 372: 423-428.CrossRefPubMed

Title: Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease
Authors: Christopher A Bates
Wei Zheng
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Fluids and Barriers of the CNS / Issue 1/2014
Electronic ISSN: 2045-8118
DOI: https://doi.org/10.1186/2045-8118-11-17

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Brain disposition of α-Synuclein: roles of brain barrier systems and implications for Parkinson’s disease

Abstract

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