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Retina as a Model to Study In Vivo Transmission of α-Synuclein in the A53T Mouse Model of Parkinson’s Disease

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Mouse Genetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2224))

Abstract

Parkinson’s disease is a neurodegenerative disorder characterized by accumulation of misfolded α-synuclein within the central nervous system (CNS). Retinal manifestations have been widely described as a prodromal symptom; however, we have a limited understanding of the retinal pathology associated with Parkinson’s disease. The strong similarities between the retina and the brain and the accessibility of the retina has potentiated studies to investigate retinal pathology in an effort to identify biomarkers for early detection, as well as for monitoring the progression of disease and efficacy of therapies as they become available. Here, we discuss a study conducted using a transgenic mouse model of Parkinson’s disease (TgM83, expressing human α-synuclein containing the familial PD-associated A53T mutation) to demonstrate the effect of the A53T α-synuclein mutation on the retina. Additionally, we show that “seeding” with brain homogenates from clinically ill TgM83 mice accelerates the accumulation of retinal α-synuclein. The work described in this chapter provides insight into retinal changes associated with Parkinson’s disease and identifies retinal indicators of Parkinson’s disease pathogenesis that could serve as potential biomarkers for early detection.

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References

  1. Recasens A, Dehay B (2014) Alpha-synuclein spreading in Parkinson’s disease. Front Neuroanat 8:159

    Article  PubMed  PubMed Central  Google Scholar 

  2. Parkinson J (2002) An essay on the shaking palsy. J Neuropsychiatry Clin Neurosci 14(2):223–236

    Article  PubMed  Google Scholar 

  3. Kempster PA, Hurwitz B, Lees AJ (2007) A new look at James Parkinson's Essay on the Shaking Palsy. Neurology 69(5):482–485

    Article  PubMed  Google Scholar 

  4. Rocca WA (2018) The burden of Parkinson’s disease: a worldwide perspective. Lancet Neurol 17(11):928–929

    Article  PubMed  Google Scholar 

  5. Braak H et al (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134

    Article  PubMed  Google Scholar 

  6. Guo L et al (2018) Oculo-visual abnormalities in Parkinson’s disease: possible value as biomarkers. Mov Disord 33(9):1390–1406

    Article  PubMed  Google Scholar 

  7. Mahlknecht P, Seppi K, Poewe W (2015) The concept of prodromal Parkinson’s disease. J Parkinsons Dis 5(4):681–697

    Article  PubMed  PubMed Central  Google Scholar 

  8. Poewe W (2008) Non-motor symptoms in Parkinson’s disease. Eur J Neurol 15:14–20

    Article  PubMed  Google Scholar 

  9. Armstrong RA (2011) Visual symptoms in Parkinson’s disease. Parkinson’s Dis 2011:908306

    CAS  Google Scholar 

  10. Archibald NK et al (2009) The retina in Parkinson’s disease. Brain 132(5):1128–1145

    Article  PubMed  Google Scholar 

  11. Bodis-Wollner I (2013) Foveal vision is impaired in Parkinson’s disease. Parkinsonism Relat Disord 19(1):1–14

    Article  PubMed  Google Scholar 

  12. Ridder A et al (2017) Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease. Parkinsonism Relat Disord 34:15–19

    Article  CAS  PubMed  Google Scholar 

  13. Jones RD, Donaldson IM, Timmings PL (1992) Impairment of high-contrast visual acuity in Parkinson’s disease. Mov Disord 7(3):232–238

    Article  CAS  PubMed  Google Scholar 

  14. Matsui H et al (2006) Impaired visual acuity as a risk factor for visual hallucinations in Parkinson’s disease. J Geriatr Psychiatry Neurol 19(1):36–40

    Article  PubMed  Google Scholar 

  15. Sartucci F, Porciatti V (2006) Visual-evoked potentials to onset of chromatic red-green and blue-yellow gratings in Parkinson’s disease never treated with L-dopa. J Clin Neurophysiol 23(5):431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. De Groef L, Cordeiro MF (2018) Is the eye an extension of the brain in central nervous system disease? J Ocul Pharmacol Ther 34(1-2):129–133

    Article  PubMed  CAS  Google Scholar 

  17. Normando EM et al (2016) The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson’s disease: evidence for a neuroprotective effect of rosiglitazone in the eye and brain. Acta Neuropathol Commun 4(1):86

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Schneider JS, Ault ME, Anderson DW (2014) Retinal Pathology detected by optical coherence tomography in an animal model of Parkinson's disease. Mov Disord 29(12):1547–1551

    Article  CAS  PubMed  Google Scholar 

  19. Turcano P et al (2019) Early ophthalmologic features of Parkinson’s disease: a review of preceding clinical and diagnostic markers. J Neurol 266(9):2103–2111

    Article  PubMed  Google Scholar 

  20. Bodis-Wollner I et al (2014) α-synuclein in the inner retina in parkinson disease. Ann Neurol 75(6):964–966

    Article  CAS  PubMed  Google Scholar 

  21. Bodis-Wollner I, Miri S, Glazman S (2014) Venturing into the no-man's land of the retina in Parkinson’s disease. Mov Disord 29(1):15–22

    Article  PubMed  Google Scholar 

  22. Ho CY et al (2014) Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer’s and Parkinson’s disease patients. Brain Pathol 24(1):25–32

    Article  CAS  PubMed  Google Scholar 

  23. Beach TG et al (2014) Phosphorylated α-synuclein-immunoreactive retinal neuronal elements in Parkinson’s disease subjects. Neurosci Lett 571:34–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ortuño-Lizarán I et al (2018) Phosphorylated α-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord 33(8):1315–1324

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Veys L et al (2018) Retinal α-synuclein deposits in Parkinson’s disease patients and animal models. Acta Neuropathol:1–17

    Google Scholar 

  26. Angot E et al (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9(11):1128–1138

    Article  PubMed  Google Scholar 

  27. Oueslati A (2016) Implication of alpha-synuclein phosphorylation at S129 in synucleinopathies: What have we learned in the last decade? J Parkinsons Dis 6(1):39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen L et al (2009) Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J Clin Invest 119(11):3257

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Fujiwara H et al (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4(2):160–164

    Article  CAS  PubMed  Google Scholar 

  30. Smith WW et al (2005) α-Synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J Neurosci 25(23):5544–5552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Desplats P et al (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc Natl Acad Sci 106(31):13010–13015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee S-J et al (2010) Cell-to-cell transmission of non-prion protein aggregates. Nat Rev Neurol 6(12):702

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Lee H-J et al (2008) Assembly-dependent endocytosis and clearance of extracellular a-synuclein. Int J Biochem Cell Biol 40(9):1835–1849

    Article  CAS  PubMed  Google Scholar 

  34. Dunning CJ, George S, Brundin P (2013) What’s to like about the prion-like hypothesis for the spreading of aggregated α-synuclein in Parkinson disease? Prion 7(1):92–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. El-Agnaf OM et al (2003) α-Synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J 17(13):1945–1947

    Article  CAS  PubMed  Google Scholar 

  36. Mougenot A-L et al (2012) Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 33(9):2225–2228

    Article  CAS  PubMed  Google Scholar 

  37. Luk KC et al (2012) Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949–953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Masuda-Suzukake M et al (2013) Prion-like spreading of pathological α-synuclein in brain. Brain 136(4):1128–1138

    Article  PubMed  PubMed Central  Google Scholar 

  39. Woerman AL et al (2018) α-synuclein: multiple system atrophy prions. Cold Spring Harb Perspect Med 8(7):a024588

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Katorcha E et al (2017) Cross-seeding of prions by aggregated α-synuclein leads to transmissible spongiform encephalopathy. PLoS Pathog 13(8):e1006563

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Luk KC et al (2012) Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 209(5):975–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dehay B et al (2015) Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. Lancet Neurol 14(8):855–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Oliveras-Salvá M et al (2013) rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol Neurodegener 8(1):44

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Polinski NK et al (2018) Best practices for generating and using alpha-synuclein pre-formed fibrils to model Parkinson’s disease in rodents. J Parkinson's Dis 8(2):303–322

    Article  Google Scholar 

  45. Volpicelli-Daley LA et al (2016) How can rAAV-α-synuclein and the fibril α-synuclein models advance our understanding of Parkinson's disease? J Neurochem 139:131–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Volpicelli-Daley LA et al (2011) Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72(1):57–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Okuzumi A et al (2018) Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment. Acta Neuropathol Commun 6(1):96

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Mammadova N et al (2019) Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease. Neurobiol Dis 121:1–16

    Article  CAS  PubMed  Google Scholar 

  49. Specht CG, Schoepfer R (2001) Deletion of the alpha-synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci 2(1):11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sargent D et al (2017) ‘prion-like’propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum. J Neurochem 143(1):126–135

    Article  CAS  PubMed  Google Scholar 

  51. Bétemps D et al (2015) Detection of disease-associated α-synuclein by enhanced ELISA in the brain of transgenic mice overexpressing human A53T mutated α-synuclein. J Vis Exp 99:e52752

    Google Scholar 

  52. Mougenot A-LJ et al (2011) Transmission of prion strains in a transgenic mouse model overexpressing human A53T mutated α-synuclein. J Neuropathol Exp Neurol 70(5):377–385

    Article  CAS  PubMed  Google Scholar 

  53. Mahajan VB et al (2011) Mouse eye enucleation for remote high-throughput phenotyping. J Vis Exp 57:e3184

    Google Scholar 

  54. Guo H et al (2012) An efficient procedure for protein extraction from formalin-fixed, paraffin-embedded tissues for reverse phase protein arrays. Proteome Sci 10(1):56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Virus and Prion Research Unit, United States Department of Agriculture, National Animal Disease Center, Agricultural Research Service, Ames, IA, USA

    Najiba Mammadova & Justin J. Greenlee

  2. Anses, Laboratoire de Lyon, Unité Maladies Neurodégénératives, Lyon, France

    Thierry Baron & Jérémy Verchère

  3. Department of Biomedical Sciences, Iowa State University College of Veterinary Medicine, Ames, IA, USA

    M. Heather West Greenlee

Authors
  1. Najiba Mammadova
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  2. Thierry Baron
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  3. Jérémy Verchère
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  4. Justin J. Greenlee
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  5. M. Heather West Greenlee
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Corresponding author

Correspondence to Najiba Mammadova .

Editor information

Editors and Affiliations

  1. Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA

    Shree Ram Singh

  2. Department of Surgery, University of California, AntiCancer, Inc., San Diego, CA, USA

    Robert M. Hoffman

  3. Department of Biology, University of Dayton, Dayton, OH, USA

    Amit Singh

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Mammadova, N., Baron, T., Verchère, J., Greenlee, J.J., Greenlee, M.H.W. (2021). Retina as a Model to Study In Vivo Transmission of α-Synuclein in the A53T Mouse Model of Parkinson’s Disease. In: Singh, S.R., Hoffman, R.M., Singh, A. (eds) Mouse Genetics . Methods in Molecular Biology, vol 2224. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1008-4_5

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  • DOI: https://doi.org/10.1007/978-1-0716-1008-4_5

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1007-7

  • Online ISBN: 978-1-0716-1008-4

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