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Brain Structure and Function

, Volume 217, Issue 2, pp 447–458 | Cite as

α-Synuclein in the olfactory system of a mouse model of Parkinson’s disease: correlation with olfactory projections

  • Isabel Ubeda-Bañon
  • Daniel Saiz-Sanchez
  • Carlos de la Rosa-Prieto
  • Alino Martinez-Marcos
Original Article

Abstract

Olfactory deficits are an early feature of Parkinson’s disease (PD). Neuropathologically, α-synucleinopathy (Lewy bodies and neurites) is observed earlier (stage 1) in the olfactory system than in the substantia nigra (stage 3), and this could underlies the early olfactory symptoms. In the present report, we analyzed the distribution of α-synuclein deposits in tertiary olfactory structures (anterior olfactory nucleus, olfactory tubercle, piriform cortex, posterolateral cortical amygdala and lateral entorhinal cortex) of homozygous transgenic mice (aged 2–8 months) overexpressing the human A53T variant of α-synuclein. To address the hypothesis of progressive α-synucleinopathy within the olfactory system, the distribution of α-synuclein was analyzed in conjunction with tracer injections into the main olfactory bulb. The time-course of α-synuclein expression revealed a significant increase in the piriform cortex at the age of 8 months compared to other brain structures. Tracing experiments revealed that olfactory projections are reduced in homozygous as compared to wild type animals. Double-labeling experiments show labeled axonal collaterals of mitral cells entering layer II of the piriform cortex in close proximity to α-synuclein-positive cells. To our knowledge, this is the first study addressing the progression of α-synuclein expression in a vulnerable neuronal pathway in PD.

Keywords

α-Synuclein Anosmia Olfactory deficit Olfactory projections Olfactory system Parkinson’s disease Transgenic mice Tract-tracing 

Notes

Acknowledgments

This study was supported by the Spanish Ministry of Science and Innovation (BFU2010-15729) and the Autonomous Government of Castilla-La Mancha-FEDER (PEIC11-0045-4490). The authors would like to thank the laboratory of Dr. Calvo for their assistance in genotyping animals. The English version of this manuscript was corrected by International Science Editing. This work constitutes part of the Doctoral Thesis of Isabel Úbeda-Bañón.

References

  1. Angot E et al (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9:1128–1138PubMedCrossRefGoogle Scholar
  2. Ansari KA, Johnson A (1975) Olfactory function in patients with Parkinson’s disease. J Chronic Dis 28:493–497PubMedCrossRefGoogle Scholar
  3. Beach TG et al (2009) Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117:169–174PubMedCrossRefGoogle Scholar
  4. Benarroch EE (2010) Olfactory system: functional organization and involvement in neurodegenerative disease. Neurology 75:1104–1109PubMedCrossRefGoogle Scholar
  5. Braak H et al (2003a) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  6. Braak H et al (2003b) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536PubMedCrossRefGoogle Scholar
  7. Braak H et al (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72PubMedCrossRefGoogle Scholar
  8. Brundin P et al (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9:741–745PubMedCrossRefGoogle Scholar
  9. Brunjes PC et al (2005) A field guide to the anterior olfactory nucleus (cortex). Brain Res Brain Res Rev 50:305–335PubMedCrossRefGoogle Scholar
  10. Constantinidis J, de Ajuriaguerra J (1970) Familial syndrome with parkinsonian tremor and anosmia and its therapy with l-dopa associated with a decarboxylase inhibitor. Therapeutique 46:263–269PubMedGoogle Scholar
  11. Daniel SE, Hawkes CH (1992) Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology. Lancet 340:186PubMedCrossRefGoogle Scholar
  12. Davis BJ et al (1978) Efferents and centrifugal afferents of the main and accessory olfactory bulbs in the hamster. Brain Res Bull 3:59–72PubMedCrossRefGoogle Scholar
  13. Dawson T et al (2002) Animal models of PD: pieces of the same puzzle? Neuron 35:219–222PubMedCrossRefGoogle Scholar
  14. Deierborg T et al (2008) Emerging restorative treatments for Parkinson’s disease. Prog Neurobiol 85:407–432PubMedCrossRefGoogle Scholar
  15. Del Tredici K et al (2002) Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426PubMedGoogle Scholar
  16. Devor M (1976) Fiber trajectories of olfactory bulb efferents in the hamster. J Comp Neurol 166:31–47PubMedCrossRefGoogle Scholar
  17. Duda JE (2010) Olfactory system pathology as a model of Lewy neurodegenerative disease. J Neurol Sci 289:49–54PubMedCrossRefGoogle Scholar
  18. Fahn S (2008) The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord 23(Suppl 3):S497–S508PubMedCrossRefGoogle Scholar
  19. Fleming SM et al (2005) Genetic mouse models of parkinsonism: strengths and limitations. NeuroRx 2:495–503PubMedCrossRefGoogle Scholar
  20. Fleming SM et al (2008) Olfactory deficits in mice overexpressing human wildtype alpha-synuclein. Eur J Neurosci 28:247–256PubMedCrossRefGoogle Scholar
  21. Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates. Elsevier, San DiegoGoogle Scholar
  22. Giasson BI et al (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533PubMedCrossRefGoogle Scholar
  23. Gutierrez-Castellanos N et al (2010) Chemosensory function of the amygdala. Vitam Horm 83:165–196PubMedCrossRefGoogle Scholar
  24. Haehner A et al (2007) Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord 22:839–842PubMedCrossRefGoogle Scholar
  25. Hawkes CH (2008) The prodromal phase of sporadic Parkinson’s disease: does it exist and if so how long is it? Mov Disord 23:1799–1807PubMedCrossRefGoogle Scholar
  26. Hawkes CH, Shephard BC (1993) Selective anosmia in Parkinson’s disease? Lancet 341:435–436PubMedCrossRefGoogle Scholar
  27. Hubbard PS et al (2007) Alpha-synuclein pathology in the olfactory pathways of dementia patients. J Anat 211:117–124PubMedCrossRefGoogle Scholar
  28. Katzenschlager R, Lees AJ (2004) Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr Opin Neurol 17:417–423PubMedCrossRefGoogle Scholar
  29. Kim YH et al (2011) Inducible dopaminergic glutathione depletion in an alpha-synuclein transgenic mouse model results in age-related olfactory dysfunction. Neuroscience 172:379–386PubMedCrossRefGoogle Scholar
  30. Kordower JH et al (2008) Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord 23:2303–2306PubMedCrossRefGoogle Scholar
  31. Kranick SM, Duda JE (2008) Olfactory dysfunction in Parkinson’s disease. Neurosignals 16:35–40PubMedCrossRefGoogle Scholar
  32. Lee MK et al (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A. 99:8968–8973PubMedCrossRefGoogle Scholar
  33. Lees AJ et al (2009) Parkinson’s disease. Lancet 373:2055–2066PubMedCrossRefGoogle Scholar
  34. Lerner A, Bagic A (2008) Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord 23:1076–1084PubMedCrossRefGoogle Scholar
  35. Li JY et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503PubMedCrossRefGoogle Scholar
  36. Marek K, Jennings D (2009) Can we image premotor Parkinson disease? Neurology 72:S21–S26PubMedCrossRefGoogle Scholar
  37. Martinez-Marcos A (2009) On the organization of olfactory and vomeronasal cortices. Prog Neurobiol 87:21–30PubMedCrossRefGoogle Scholar
  38. Martinez-Marcos A, Halpern M (2006) Efferent connections of the main olfactory bulb in the opossum (Monodelphis domestica): a characterization of the olfactory entorhinal cortex in a marsupial. Neurosci Lett 395:51–56PubMedCrossRefGoogle Scholar
  39. Morley JF, Duda JE (2010) Olfaction as a biomarker in Parkinson’s disease. Biomark Med 4:661–670PubMedCrossRefGoogle Scholar
  40. Morley JF, Hurtig HI (2010) Current understanding and management of Parkinson disease: five new things. Neurology 75:S9–S15PubMedCrossRefGoogle Scholar
  41. Müller A et al (2002) Olfactory function in Parkinsonian syndromes. J Clin Neurosci 9:521–524PubMedCrossRefGoogle Scholar
  42. Pearce RK et al (1995) The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 10:283–287PubMedCrossRefGoogle Scholar
  43. Ponsen MM et al (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56:173–181PubMedCrossRefGoogle Scholar
  44. Richfield EK et al (2002) Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol 175:35–48PubMedCrossRefGoogle Scholar
  45. Ross GW et al (2008) Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann Neurol 63:167–173PubMedCrossRefGoogle Scholar
  46. Saiz-Sanchez D et al (2010) Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol 223:347–350PubMedCrossRefGoogle Scholar
  47. Saiz-Sanchez D et al (2010a) The human olfactory system: an anatomical and cytoarchitectonic study of the anterior olfactory nucleus. In: Flynn CE, Callaghan BR (eds) Neuroanatomy Research Advances, New York, p 171–182Google Scholar
  48. Savica R et al (2010) When does Parkinson disease start? Arch Neurol 67:798–801PubMedCrossRefGoogle Scholar
  49. Sengoku R et al (2008) Incidence and extent of Lewy body-related alpha-synucleinopathy in aging human olfactory bulb. J Neuropathol Exp Neurol 67:1072–1083PubMedCrossRefGoogle Scholar
  50. Shipley MT, Adamek GD (1984) The connections of the mouse olfactory bulb: a study using orthograde and retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase. Brain Res Bull 12:669–688PubMedCrossRefGoogle Scholar
  51. Siderowf A, Stern MB (2008) Premotor Parkinson’s disease: clinical features, detection, and prospects for treatment. Ann Neurol 64(Suppl 2):S139–S147PubMedGoogle Scholar
  52. Silveira-Moriyama L et al (2009) Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci Lett 453:77–80PubMedCrossRefGoogle Scholar
  53. Skeen LC, Hall WC (1977) Efferent projections of the main and the accessory olfactory bulb in the tree shrew (Tupaia glis). J Comp Neurol 172:1–35PubMedCrossRefGoogle Scholar
  54. Sommer B et al (2000) Mouse models of alpha-synucleinopathy and Lewy pathology. Exp Gerontol 35:1389–1403PubMedCrossRefGoogle Scholar
  55. Spillantini MG et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  56. Tolosa E et al (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology 72:S12–S20PubMedCrossRefGoogle Scholar
  57. Toulouse A, Sullivan AM (2008) Progress in Parkinson’s disease-where do we stand? Prog Neurobiol 85:376–392PubMedCrossRefGoogle Scholar
  58. Ubeda-Banon I et al (2010a) Alpha-synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein- and substance P-positive cells. Acta Neuropathol 119:723–735PubMedCrossRefGoogle Scholar
  59. Ubeda-Banon I et al (2010b) Staging of alpha-synuclein in the olfactory bulb in a model of Parkinson’s disease: cell types involved. Mov Disord 25:1701–1707PubMedCrossRefGoogle Scholar
  60. Ubeda-Banon I et al (2011) Cladistic analysis of olfactory and vomeronasal systems. Front Neuroanat 5:3PubMedCrossRefGoogle Scholar
  61. van der Putten H et al (2000) Neuropathology in mice expressing human alpha-synuclein. J Neurosci 20:6021–6029PubMedGoogle Scholar
  62. Vidailhet M (2011) Movement disorders in 2010: Parkinson disease-symptoms and treatments. Nat Rev Neurol 7:70–72PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Isabel Ubeda-Bañon
    • 1
  • Daniel Saiz-Sanchez
    • 1
  • Carlos de la Rosa-Prieto
    • 1
  • Alino Martinez-Marcos
    • 1
  1. 1.Departamento de Ciencias Médicas, Facultad de Medicina de Ciudad Real, Laboratorio de Neuroplasticidad y Neurodegeneración, Centro Regional de Investigaciones BiomédicasUniversidad de Castilla-La ManchaCiudad RealSpain

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