Skip to main content

Advertisement

SpringerLink
Log in

α-Synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein- and substance P-positive cells

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Hyposmia is an early symptom of idiopathic Parkinson’s disease but the pathological bases of such dysfunction are largely unknown. The distribution of α-synuclein, which forms Lewy bodies and Lewy neurites, and the types of neurons (based on their neurotransmitters) affected by α-synucleinopathy were investigated in the olfactory system in Parkinson’s disease. Immunohistochemical distribution of α-synuclein and its co-localization with tyrosine hydroxylase, somatostatin, calbindin, calretinin, parvalbumin and substance P in the olfactory bulb, anterior olfactory nucleus, olfactory tubercle and piriform, periamygdaloid and rostral entorhinal cortices of idiopathic Parkinson’s disease cases (n = 11) and age-matched controls (n = 11) were investigated. Lewy bodies and Lewy neurites were present in the olfactory bulb, particularly in mitral cells and in the inner plexiform layer. α-synuclein was particularly abundant in the different divisions of the anterior olfactory nucleus (bulbar, intrapeduncular, retrobulbar and cortical). In contrast, Lewy bodies and Lewy neurites were less abundant in the olfactory tubercle and olfactory cortices. In the olfactory bulb, anterior olfactory nucleus and olfactory cortices, cells affected by α-synucleinopathy rarely co-localized tyrosine hydroxylase or somatostatin, but they frequently co-localized calbindin, calretinin, parvalbumin and substance P. The present data provide evidence that α-synucleinopathy affects neurons along the olfactory pathway. Dopamine- and somatostatin-positive cells are rarely affected; whereas the cell types most vulnerable to neurodegeneration include glutamate- (mitral cells), calcium-binding protein- and substance P-positive cells. These results provide data on the distribution and cell types involved by α-synucleinopathy in the human olfactory system during Parkinson disease that may be useful for future clinical investigation.

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
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

ACC:

Nucleus accumbens

AON:

Anterior olfactory nucleus

AONb:

Bulbar anterior olfactory nucleus

AONcal:

Cortical anterior lateral anterior olfactory nucleus

AONcam:

Cortical anterior medial anterior olfactory nucleus

AONpal:

Cortical posterior lateral anterior olfactory nucleus

AONcpm:

Cortical posterior medial anterior olfactory nucleus

AONi:

Intrapeduncular anterior olfactory nucleus

AONr:

Retrobulbar anterior olfactory nucleus

BL:

Basolateral amygdala

BM:

Basomedial amygdala

CB:

Calbindin

Ce:

Central amydala

CR:

Calretinin

EC:

Entorhinal cortex

EPL:

External plexiform layer

GL:

Glomerular layer

GCL:

Granule cell layer

IPD:

Idiopathic Parkinson’s disease

Me:

Medial amgydala

MOB:

Main olfactory bulb

molf:

Medial olfactory radiation

NT:

Neurotrace

olfr:

Olfactory radiation

ONL:

Outer nerve layer

OP:

Olfactory peduncle

ot:

Olfactory tract

PAC:

Periamygdaloid cortex

PD:

Parkinson’s disease

Pir:

Piriform cortex

PMOL:

Posteromedial orbital lobule

PV:

Parvalbumin

S:

Subiculum

SA:

Stratum album

SG:

Straight gyrus

SMT:

Somatostatin

SP:

Substance P

SYN:

α-Synuclein

TH:

Tyrosine hydroxylase

References

  1. Attems J, Jellinger KA (2006) Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 25:265–271

    CAS  PubMed  Google Scholar 

  2. Beach TG, Adler CH, Lue L et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634

    Article  PubMed  Google Scholar 

  3. Beach TG, White CL III, Hladik CL et al (2009) Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117:169–174

    Article  CAS  PubMed  Google Scholar 

  4. Becker G, Muller A, Braune S et al (2002) Early diagnosis of Parkinson’s disease. J Neurol 249:40–48

    Article  Google Scholar 

  5. Bedard A, Parent A (2004) Evidence of newly generated neurons in the human olfactory bulb. Dev Brain Res 151:159–168

    Article  CAS  Google Scholar 

  6. Berendse HW, Ponsen MM (2006) Detection of preclinical Parkinson’s disease along the olfactory trac(t). J Neural Transm 70:321–325

    Article  CAS  Google Scholar 

  7. Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  8. Braak H, Rub U, Gai WP et al (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536

    Article  CAS  PubMed  Google Scholar 

  9. Braak H, de Vos RA, Bohl J 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 396:67–72

    Article  CAS  PubMed  Google Scholar 

  10. Braak H, Del Tredici K (2008) Cortico-basal ganglia-cortical circuitry in Parkinson’s disease reconsidered. Exp Neurol 212:226–229

    Article  PubMed  Google Scholar 

  11. Brundin P, Li JY, Holton JL et al (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9:741–745

    Article  CAS  PubMed  Google Scholar 

  12. Chaudhuri KR, Naidu Y (2008) Early Parkinson’s disease and non-motor issues. J Neurol 255:33–38

    Article  PubMed  Google Scholar 

  13. Daniel SE, Hawkes CH (1992) Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology. Lancet 340:186

    Article  CAS  PubMed  Google Scholar 

  14. Del Tredici K, Rüb U, De Vos RA et al (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426

    PubMed  Google Scholar 

  15. Doty RL (2008) The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 63:7–15

    Article  PubMed  Google Scholar 

  16. Duda JE, Shah U, Arnold SE et al (1999) The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp Neurol 160:515–522

    Article  CAS  PubMed  Google Scholar 

  17. Fahn S (2008) The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord 23(Suppl 3):S497–S508

    Article  PubMed  Google Scholar 

  18. Greffard S, Verny M, Bonnet AM et al (2010) A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol Aging 31:99–103

    Article  CAS  PubMed  Google Scholar 

  19. Haehner A, Hummel T, Hummel C et al (2007) Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord 22:839–842

    Article  PubMed  Google Scholar 

  20. Haehner A, Boesveldt S, Berendse HW et al (2009) Prevalence of smell loss in Parkinson’s disease—a multicenter study. Parkinsonism Relat Disord 15:490–494

    Article  CAS  PubMed  Google Scholar 

  21. Harding AJ, Stimson E, Henderson JM et al (2002) Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain 125:2431–2445

    Article  PubMed  Google Scholar 

  22. Hawkes CH, Shephard BC, Daniel SE (1999) Is Parkinson’s disease a primary olfactory disorder? Qjm 92:473–480

    Article  CAS  PubMed  Google Scholar 

  23. Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614

    Article  CAS  PubMed  Google Scholar 

  24. Hawkes CH (2008) The prodromal phase of sporadic Parkinson’s disease: does it exist and if so how long is it? Mov Disord 23:1799–1807

    Article  PubMed  Google Scholar 

  25. Hawkes CH, Del Tredici K, Braak H (2009) Parkinson’s disease: the dual hit theory revisited. Ann N Y Acad Sci 1170:615–622

    Article  PubMed  Google Scholar 

  26. Hawkes CH, Doty RL (2009) The Neurology of Olfaction. Cambridge University Press, Cambridge

    Book  Google Scholar 

  27. Hoogland PV, Huisman E (1999) Tyrosine hydroxylase immunoreactive structures in the aged human olfactory bulb and olfactory peduncle. J Chem Neuroanat 17:153–161

    Article  CAS  PubMed  Google Scholar 

  28. Hubbard PS, Esiri MM, Reading M et al (2007) Alpha-synuclein pathology in the olfactory pathways of dementia patients. J Anat 211:117–124

    Article  PubMed  Google Scholar 

  29. Huisman E, Uylings HB, Hoogland PV (2008) Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson’s disease patients. Mov Disord 23:1407–1413

    Article  PubMed  Google Scholar 

  30. Hummel T, Witt M, Reichmann H et al (2010) Immunohistochemical, volumetric, and functional neuroimaging studies in patients with idiopathic Parkinson’s disease. J Neurol Sci 289:119–122

    Article  CAS  PubMed  Google Scholar 

  31. Ikemoto K, Nagatsu I, Kitahama K et al (1998) A dopamine-synthesizing cell group demonstrated in the human basal forebrain by dual labeling immunohistochemical technique of tyrosine hydroxylase and aromatic L-amino acid decarboxylase. Neurosci Lett 243:129–132

    Article  CAS  PubMed  Google Scholar 

  32. Issidorides MR, Mytilineou C, Whetsell WO Jr et al (1978) Protein-rich cytoplasmic bodies of substantia nigra and locus ceruleus. A comparative study in Parkinsonian and normal brain. Arch Neurol 35:633–637

    CAS  PubMed  Google Scholar 

  33. Jellinger KA, Attems J (2005) Alzheimer pathology in the olfactory bulb. Neuropathol Appl Neurobiol 31:203

    Article  CAS  PubMed  Google Scholar 

  34. Jellinger KA (2009) Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117:215–216 (author reply 217–218)

    Article  PubMed  Google Scholar 

  35. Kranick SM, Duda JE (2008) Olfactory dysfunction in Parkinson’s disease. Neurosignals 16:35–40

    Article  CAS  PubMed  Google Scholar 

  36. Lees AJ (2007) Unresolved issues relating to the Shaking Palsy on the celebration of James Parkinson’s 250th birthday. Mov Disord 22:S327–S334

    Article  PubMed  Google Scholar 

  37. Lerner A, Bagic A (2008) Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord 23:1076–1084

    Article  PubMed  Google Scholar 

  38. Linazasoro G (2008) Olfaction testing in PD: risky conclusions. Mov Disord 23:1060

    Article  PubMed  Google Scholar 

  39. Mai JK, Paxinos G, Voss T (2008) Atlas of the human brain. Elsevier, New York

    Google Scholar 

  40. Marek K, Jennings D (2009) Can we image premotor Parkinson disease? Neurology 72:S21–S26

    Article  PubMed  Google Scholar 

  41. Michell AW, Lewis SJ, Foltynie T et al (2004) Biomarkers and Parkinson’s disease. Brain 127:1693–1705

    Article  CAS  PubMed  Google Scholar 

  42. Mosharov EV, Larsen KE, Kanter E et al (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62:218–229

    Article  CAS  PubMed  Google Scholar 

  43. Müller A, Mungersdorf M, Reichmann H et al (2002) Olfactory function in Parkinsonian syndromes. J Clin Neurosci 9:521–524

    Article  PubMed  Google Scholar 

  44. Murase S, McKay RD (2006) A specific survival response in dopamine neurons at most risk in Parkinson’s disease. J Neurosci 26:9750–9760

    Article  CAS  PubMed  Google Scholar 

  45. Ohm TG, Muller H, Ulfig N et al (1990) Glutamic-acid-decarboxylase-and parvalbumin-like-immunoreactive structures in the olfactory bulb of the human adult. J Comp Neurol 291:1–8

    Article  CAS  PubMed  Google Scholar 

  46. Ohm TG, Muller H, Braak E (1991) Calbindin-D-28k-like immunoreactive structures in the olfactory bulb and anterior olfactory nucleus of the human adult: distribution and cell typology—partial complementarity with parvalbumin. Neuroscience 42:823–840

    Article  CAS  PubMed  Google Scholar 

  47. Parkkinen L, Silveira-Moriyama L, Holton JL et al (2009) Can olfactory bulb biopsy be justified for the diagnosis of Parkinson’s disease? Comments on “olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders”. Acta Neuropathol 117:213–214 (author reply 217–218)

    Article  PubMed  Google Scholar 

  48. Pearce RK, Hawkes CH, Daniel SE (1995) The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 10:283–287

    Article  CAS  PubMed  Google Scholar 

  49. Ponsen MM, Stoffers D, Booij J et al (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56:173–181

    Article  PubMed  Google Scholar 

  50. Price JL (1990) Olfactory system. In: Paxinos G (ed) The human nervous system. Academic Press, San Diego, pp 979–998

    Google Scholar 

  51. Ross GW, Abbott RD, Petrovitch H et al (2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21:2062–2067

    Article  PubMed  Google Scholar 

  52. Saiz-Sanchez D, Ubeda-Banon I, de la Rosa-Prieto C et al. (2010) Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol. doi:10.1016/j.expneurol.2009.06.010

  53. Sengoku R, Saito Y, Ikemura M et al (2008) Incidence and extent of Lewy body-related alpha-synucleinopathy in aging human olfactory bulb. J Neuropathol Exp Neurol 67:1072–1083

    Article  PubMed  Google Scholar 

  54. Silveira-Moriyama L, Holton JL, Kingsbury A et al (2009) Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci Lett 453:77–80

    Article  CAS  PubMed  Google Scholar 

  55. Smith RL, Baker H, Kolstad K et al (1991) Localization of tyrosine hydroxylase and olfactory marker protein immunoreactivities in the human and macaque olfactory bulb. Brain Res 548:140–148

    Article  CAS  PubMed  Google Scholar 

  56. Smith RL, Baker H, Greer CA (1993) Immunohistochemical analyses of the human olfactory bulb. J Comp Neurol 333:519–530

    Article  CAS  PubMed  Google Scholar 

  57. Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  CAS  PubMed  Google Scholar 

  58. Stern MB (2004) The preclinical detection of Parkinson’s disease: ready for prime time? Ann Neurol 56:169–171

    Article  PubMed  Google Scholar 

  59. Stiasny-Kolster K, Doerr Y, Moller JC et al (2005) Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128:126–137

    Article  CAS  PubMed  Google Scholar 

  60. Tolosa E, Compta Y, Gaig C (2007) The premotor phase of Parkinson’s disease. Parkinsonism Relat Disord 13(Suppl):S2–S7

    Article  PubMed  Google Scholar 

  61. Tolosa E, Gaig C, Santamaria J et al (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology 72:S12–S20

    Article  PubMed  Google Scholar 

  62. Witt M, Bormann K, Gudziol V et al (2009) Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord 24:906–914

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The tissue was obtained from the Banc de Teixits Neurològics, Univ. Barcelona-Hospital Clínic and from the Banco de Tejidos/Fundación para investigaciones neurológicas, Univ. Complutense de Madrid. The authors thank members of LNH. International Science Editing revised the English version of the manuscript. The authors are indebted to Dr. Mimi Halpern for reading and commenting on the manuscript. Supported by the Autonomous Government of Castilla-La Mancha/FEDER [grants PI-2006/15 and PCC08-0064]. Authors declare no conflict of interests. This work is part of the Doctoral Thesis of Isabel Úbeda-Bañón.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratorio de Neuroanatomía Humana, Facultad de Medicina/Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, 02006, Albacete, Spain

    Isabel Ubeda-Bañon, Daniel Saiz-Sanchez, Carlos de la Rosa-Prieto & Alino Martinez-Marcos

  2. Servicio de Neurología, Complejo Hospitalario Universitario, 02006, Albacete, Spain

    Lucia Argandoña-Palacios & Susana Garcia-Muñozguren

Authors
  1. Isabel Ubeda-Bañon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Saiz-Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos de la Rosa-Prieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucia Argandoña-Palacios
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susana Garcia-Muñozguren
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alino Martinez-Marcos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alino Martinez-Marcos.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 36 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ubeda-Bañon, I., Saiz-Sanchez, D., de la Rosa-Prieto, C. et al. α-Synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein- and substance P-positive cells. Acta Neuropathol 119, 723–735 (2010). https://doi.org/10.1007/s00401-010-0687-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0687-9

Keywords

Search

Navigation