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Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2019

Open Access 01-12-2019 | Parkinson's Disease | Research

Efficient RT-QuIC seeding activity for α-synuclein in olfactory mucosa samples of patients with Parkinson’s disease and multiple system atrophy

Authors: Chiara Maria Giulia De Luca, Antonio Emanuele Elia, Sara Maria Portaleone, Federico Angelo Cazzaniga, Martina Rossi, Edoardo Bistaffa, Elena De Cecco, Joanna Narkiewicz, Giulia Salzano, Olga Carletta, Luigi Romito, Grazia Devigili, Paola Soliveri, Pietro Tiraboschi, Giuseppe Legname, Fabrizio Tagliavini, Roberto Eleopra, Giorgio Giaccone, Fabio Moda

Published in: Translational Neurodegeneration | Issue 1/2019

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Abstract

Background

Parkinson’s disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal α-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either α-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of α-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM).

Methods

We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant α-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce α-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.

Results

Our results showed that a significant percentage of MSA and PD samples induced α-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.

Conclusions

Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for α-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages.
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Literature
1.
2.
Safarpour D, Willis AW. Clinical epidemiology, evaluation, and Management of Dementia in Parkinson disease. Am J Alzheimers Dis Other Dement. 2016;31(7):585–94.CrossRef
3.
Levin J, Kurz A, Arzberger T, Giese A, Hoglinger GU. The differential diagnosis and treatment of atypical parkinsonism. Dtsch Arztebl Int. 2016;113(5):61–9.PubMedPubMedCentral
4.
Bhidayasiri R, Rattanachaisit W, Phokaewvarangkul O, Lim TT, Fernandez HH. Exploring bedside clinical features of parkinsonism: a focus on differential diagnosis. Parkinsonism Relat Disord. 2018.
5.
McFarland NR. Diagnostic Approach to Atypical Parkinsonian Syndromes. Continuum (Minneap Minn). 2016;22(4 Movement Disorders):1117–42.
6.
7.
8.
Dickson DW. Neuropathology of Parkinson disease. Parkinsonism Relat Disord. 2018;46(Suppl 1):S30–S3.PubMedCrossRef
9.
Ubhi K, Peng K, Lessig S, Estrella J, Adame A, Galasko D, et al. Neuropathology of dementia with Lewy bodies in advanced age: a comparison with Alzheimer disease. Neurosci Lett. 2010;485(3):222–7.PubMedPubMedCentralCrossRef
10.
Pappolla MA. Lewy bodies of Parkinson’s disease. Immune electron microscopic demonstration of neurofilament antigens in constituent filaments. Arch Pathol Lab Med. 1986;110(12):1160–3.PubMed
11.
Pappolla MA, Shank DL, Alzofon J, Dudley AW. Colloid (hyaline) inclusion bodies in the central nervous system: their presence in the substantia nigra is diagnostic of Parkinson's disease. Hum Pathol. 1988;19(1):27–31.PubMedCrossRef
12.
Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, et al. Alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015;522(7556):340–4.PubMedCrossRef
13.
14.
Jellinger KA. Neuropathological spectrum of synucleinopathies. Mov Disord. 2003;18(Suppl 6):S2–12.PubMedCrossRef
15.
Peelaerts W, Bousset L, Baekelandt V, Melki R. A-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. 2018;373(1):195–212.PubMedCrossRef
16.
Lawton M, Baig F, Rolinski M, Ruffman C, Nithi K, May MT, et al. Parkinson's disease subtypes in the Oxford Parkinson disease Centre (OPDC) discovery cohort. J Park Dis. 2015;5(2):269–79.
17.
Woerman AL, Kazmi SA, Patel S, Freyman Y, Oehler A, Aoyagi A, et al. MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol. 2018;135(1):49–63.PubMedCrossRef
18.
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591–601.PubMedCrossRef
19.
Rizzo G, Copetti M, Arcuti S, Martino D, Fontana A, Logroscino G. Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis. Neurology. 2016;86(6):566–76.PubMedCrossRef
20.
Parkinson J. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci. 2002;14(2):223–36 discussion 2.PubMedCrossRef
21.
Uchikado H, DelleDonne A, Ahmed Z, Dickson DW. Lewy bodies in progressive supranuclear palsy represent an independent disease process. J Neuropathol Exp Neurol. 2006;65(4):387–95.PubMedCrossRef
22.
Uchikado H, Lin WL, DeLucia MW, Dickson DW. Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol. 2006;65(7):685–97.PubMedCrossRef
23.
Mori H, Oda M, Komori T, Arai N, Takanashi M, Mizutani T, et al. Lewy bodies in progressive supranuclear palsy. Acta Neuropathol. 2002;104(3):273–8.PubMed
24.
Kasanuki K, Josephs KA, Ferman TJ, Murray ME, Koga S, Konno T, et al. Diffuse Lewy body disease manifesting as corticobasal syndrome: a rare form of Lewy body disease. Neurology. 2018;91(3):e268–e79.PubMedPubMedCentralCrossRef
25.
Yamashita S, Sakashita N, Yamashita T, Tawara N, Tasaki M, Kawakami K, et al. Concomitant accumulation of alpha-synuclein and TDP-43 in a patient with corticobasal degeneration. J Neurol. 2014;261(11):2209–17.PubMedCrossRef
26.
Nagaishi M, Yokoo H, Nakazato Y. Tau-positive glial cytoplasmic granules in multiple system atrophy. Neuropathology. 2011;31(3):299–305.PubMedCrossRef
27.
Cairns NJ, Atkinson PF, Hanger DP, Anderton BH, Daniel SE, Lantos PL. Tau protein in the glial cytoplasmic inclusions of multiple system atrophy can be distinguished from abnormal tau in Alzheimer's disease. Neurosci Lett. 1997;230(1):49–52.PubMedCrossRef
28.
Lei P, Ayton S, Finkelstein DI, Adlard PA, Masters CL, Bush AI. Tau protein: relevance to Parkinson's disease. Int J Biochem Cell Biol. 2010;42(11):1775–8.PubMedCrossRef
29.
Bancher C, Braak H, Fischer P, Jellinger KA. Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer's and Parkinson's disease patients. Neurosci Lett. 1993;162(1–2):179–82.PubMedCrossRef
30.
Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, et al. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology. 2014;83(5):406–12.PubMedPubMedCentralCrossRef
31.
Litvan I, Goetz CG, Jankovic J, Wenning GK, Booth V, Bartko JJ, et al. What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study. Arch Neurol. 1997;54(8):937–44.PubMedCrossRef
32.
Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, et al. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology. 2015;85(5):404–12.PubMedPubMedCentralCrossRef
33.
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670–6.PubMedPubMedCentralCrossRef
34.
Palma JA, Norcliffe-Kaufmann L, Kaufmann H. Diagnosis of multiple system atrophy. Auton Neurosci. 2018;211:15–25.PubMedCrossRef
35.
Litvan I, Campbell G, Mangone CA, Verny M, McKee A, Chaudhuri KR, et al. Which clinical features differentiate progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) from related disorders? A clinicopathological study. Brain. 1997;120(Pt 1):65–74.PubMedCrossRef
36.
Osaki Y, Ben-Shlomo Y, Lees AJ, Daniel SE, Colosimo C, Wenning G, et al. Accuracy of clinical diagnosis of progressive supranuclear palsy. Mov Disord. 2004;19(2):181–9.PubMedCrossRef
37.
Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996;47(1):1–9.PubMedCrossRef
38.
Lopez OL, Litvan I, Catt KE, Stowe R, Klunk W, Kaufer DI, et al. Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias. Neurology. 1999;53(6):1292–9.PubMedCrossRef
39.
Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord. 2017;32(6):853–64.PubMedPubMedCentralCrossRef
40.
Alexander SK, Rittman T, Xuereb JH, Bak TH, Hodges JR, Rowe JB. Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J Neurol Neurosurg Psychiatry. 2014;85(8):925–9.PubMedCrossRef
41.
42.
Atarashi R, Wilham JM, Christensen L, Hughson AG, Moore RA, Johnson LM, et al. Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking. Nat Methods. 2008;5(3):211–2.PubMedCrossRef
43.
Fairfoul G, McGuire LI, Pal S, Ironside JW, Neumann J, Christie S, et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 2016;3(10):812–8.PubMedPubMedCentralCrossRef
44.
Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, Trenkwalder C, et al. Development of a biochemical diagnosis of Parkinson disease by detection of alpha-Synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol. 2017;74(2):163–72.PubMedCrossRef
45.
Groveman BR, Orru CD, Hughson AG, Raymond LD, Zanusso G, Ghetti B, et al. Rapid and ultra-sensitive quantitation of disease-associated alpha-synuclein seeds in brain and cerebrospinal fluid by alphaSyn RT-QuIC. Acta Neuropathol Commun. 2018;6(1):7.PubMedPubMedCentralCrossRef
46.
Saijo E, Ghetti B, Zanusso G, Oblak A, Furman JL, Diamond MI, et al. Ultrasensitive and selective detection of 3-repeat tau seeding activity in pick disease brain and cerebrospinal fluid. Acta Neuropathol. 2017;133(5):751–65.PubMedCrossRef
47.
Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. 2010;11(3):155–9.PubMedCrossRef
48.
49.
Aulic S, Le TT, Moda F, Abounit S, Corvaglia S, Casalis L, et al. Defined alpha-synuclein prion-like molecular assemblies spreading in cell culture. BMC Neurosci. 2014;15:69.PubMedPubMedCentralCrossRef
50.
Ayers JI, Giasson BI, Borchelt DR. Prion-like spreading in Tauopathies. Biol Psychiatry. 2018;83(4):337–46.PubMedCrossRef
51.
52.
Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science. 2007;318(5852):930–6.PubMedCrossRef
53.
Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009;106(31):13010–5.PubMedPubMedCentralCrossRef
54.
Freundt EC, Maynard N, Clancy EK, Roy S, Bousset L, Sourigues Y, et al. Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport. Ann Neurol. 2012;72(4):517–24.PubMedPubMedCentralCrossRef
55.
Peelaerts W, Baekelandt V. a-Synuclein strains and the variable pathologies of synucleinopathies. J Neurochem. 2016;139(Suppl 1):256–74.PubMedCrossRef
56.
Holmes BB, Diamond MI. Prion-like properties of tau protein: the importance of extracellular tau as a therapeutic target. J Biol Chem. 2014;289(29):19855–61.PubMedPubMedCentralCrossRef
57.
Atarashi R, Satoh K, Sano K, Fuse T, Yamaguchi N, Ishibashi D, et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med. 2011;17(2):175–8.PubMedCrossRef
58.
Khurana R, Coleman C, Ionescu-Zanetti C, Carter SA, Krishna V, Grover RK, et al. Mechanism of thioflavin T binding to amyloid fibrils. J Struct Biol. 2005;151(3):229–38.PubMedCrossRef
59.
Arnold SE, Lee EB, Moberg PJ, Stutzbach L, Kazi H, Han LY, et al. Olfactory epithelium amyloid-beta and paired helical filament-tau pathology in Alzheimer disease. Ann Neurol. 2010;67(4):462–9.PubMedPubMedCentralCrossRef
60.
Green AJE, Zanusso G. Prion protein amplification techniques. Handb Clin Neurol. 2018;153:357–70.PubMedCrossRef
61.
Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology. 2001;57(8):1497–9.PubMedCrossRef
62.
Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496–503.PubMedPubMedCentralCrossRef
63.
Orru CD, Bongianni M, Tonoli G, Ferrari S, Hughson AG, Groveman BR, et al. A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med. 2014;371(6):519–29.PubMedPubMedCentralCrossRef
64.
Bandopadhyay R. Sequential extraction of soluble and insoluble alpha-Synuclein from parkinsonian brains. J Vis Exp. 2016;107.
65.
Lothian A, Lago L, Mukherjee S, Connor AR, Fowler C, McLean CA, et al. Characterization of the metal status of natively purified alpha-synuclein from human blood, brain tissue, or recombinant sources using size exclusion ICP-MS reveals no significant binding of cu. Fe or Zn Metallomics. 2019;11(1):128–40.PubMedCrossRef
66.
Trimmer PA, Borland MK, Keeney PM, Bennett JP Jr, Parker WD Jr. Parkinson's disease transgenic mitochondrial cybrids generate Lewy inclusion bodies. J Neurochem. 2004;88(4):800–12.PubMedCrossRef
67.
Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I, Dzaferbegovic H, et al. Reversible conformational conversion of alpha-Synuclein into toxic assemblies by glucosylceramide. Neuron. 2018;97(1):92–107 e10.PubMedCrossRef
68.
Brannstrom K, Lindhagen-Persson M, Gharibyan AL, Iakovleva I, Vestling M, Sellin ME, et al. A generic method for design of oligomer-specific antibodies. PLoS One. 2014;9(3):e90857.PubMedPubMedCentralCrossRef
69.
Redaelli V, Bistaffa E, Zanusso G, Salzano G, Sacchetto L, Rossi M, et al. Detection of prion seeding activity in the olfactory mucosa of patients with fatal familial insomnia. Sci Rep. 2017;7:46269.PubMedPubMedCentralCrossRef
70.
Yamasaki TR, Holmes BB, Furman JL, Dhavale DD, Su BW, Song ES, et al. Parkinson's disease and multiple system atrophy have distinct alpha-synuclein seed characteristics. J Biol Chem. 2019;294(3):1045–58.PubMedCrossRef
71.
Orru CD, Yuan J, Appleby BS, Li B, Li Y, Winner D, et al. Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med. 2017;9:eaam7785–417.PubMedPubMedCentralCrossRef
72.
Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C. Detection of misfolded Abeta oligomers for sensitive biochemical diagnosis of Alzheimer's disease. Cell Rep. 2014;7(1):261–8.PubMedCrossRef
73.
Mandal PK, Pettegrew JW, Masliah E, Hamilton RL, Mandal R. Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease. Neurochem Res. 2006;31(9):1153–62.PubMedCrossRef
74.
Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, et al. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson’s diseases. PLoS One. 2008;3(9):e3135.PubMedPubMedCentralCrossRef
75.
Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM. Synergistic interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010;30(21):7281–9.PubMedPubMedCentralCrossRef
76.
Ono K, Takahashi R, Ikeda T, Yamada M. Cross-seeding effects of amyloid beta-protein and alpha-synuclein. J Neurochem. 2012;122(5):883–90.PubMedCrossRef
77.
Young E, Westerberg B, Yanai A, Gregory-Evans K. The olfactory mucosa: a potential source of stem cells for hearing regeneration. Regen Med. 2018;13(5):581–93.PubMedCrossRef
78.
Ma Q, Ineichen BV, Detmar M, Proulx ST. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice. Nat Commun. 2017;8(1):1434.PubMedPubMedCentralCrossRef
79.
Foltynie T, Brayne C, Barker RA. The heterogeneity of idiopathic Parkinson's disease. J Neurol. 2002;249(2):138–45.PubMedCrossRef
80.
Peng C, Gathagan RJ, Lee VM. Distinct alpha-Synuclein strains and implications for heterogeneity among alpha-Synucleinopathies. Neurobiol Dis. 2018;109(Pt B):209–218.
81.
82.
Candelise N, Schmitz M, Llorens F, Villar-Pique A, Cramm M, Thom T, et al. Seeding variability of different alpha synuclein strains in synucleinopathies. Ann Neurol. 2019;85(5):691–703.PubMedCrossRef
83.
van Rumund A, Green AJE, Fairfoul G, Esselink RAJ, Bloem BR, Verbeek MM. Alpha-Synuclein real-time quaking-induced conversion in the cerebrospinal fluid of uncertain cases of parkinsonism. Ann Neurol. 2019;85(5):777–81.PubMedPubMedCentralCrossRef
84.
Zijlmans JC, Daniel SE, Hughes AJ, Revesz T, Lees AJ. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for diagnosis. Mov Disord. 2004;19(6):630–40.PubMedCrossRef
85.
Katzenschlager R, Zijlmans J, Evans A, Watt H, Lees AJ. Olfactory function distinguishes vascular parkinsonism from Parkinson's disease. J Neurol Neurosurg Psychiatry. 2004;75(12):1749–52.PubMedPubMedCentralCrossRef
Metadata
Title
Efficient RT-QuIC seeding activity for α-synuclein in olfactory mucosa samples of patients with Parkinson’s disease and multiple system atrophy
Authors
Chiara Maria Giulia De Luca
Antonio Emanuele Elia
Sara Maria Portaleone
Federico Angelo Cazzaniga
Martina Rossi
Edoardo Bistaffa
Elena De Cecco
Joanna Narkiewicz
Giulia Salzano
Olga Carletta
Luigi Romito
Grazia Devigili
Paola Soliveri
Pietro Tiraboschi
Giuseppe Legname
Fabrizio Tagliavini
Roberto Eleopra
Giorgio Giaccone
Fabio Moda
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2019
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-019-0164-x

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