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Proteomic analysis of tear fluid reveals disease-specific patterns in patients with Parkinson's disease – A pilot study

  • Author Footnotes
    1 Contributed equally.
    Matthias Boerger
    Footnotes
    1 Contributed equally.
    Affiliations
    Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
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  • Author Footnotes
    1 Contributed equally.
    Sebastian Funke
    Footnotes
    1 Contributed equally.
    Affiliations
    Department of Ophthalmology, University Medical Center Mainz, Experimental and Translational Ophthalmology, Mainz, Germany
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  • Andreas Leha
    Affiliations
    Department of Medical Statistics, University Göttingen, Facility for Medical Biometry and Statistical Bioinformatics, Göttingen, Germany
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  • Anna-Elisa Roser
    Affiliations
    Department of Neurology, University Medical Center Göttingen, Göttingen, Germany

    Deutsche Forschungsgemeinschaft - German Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany
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  • Ann-Katrin Wuestemann
    Affiliations
    Department of Ophthalmology, University Medical Center Mainz, Experimental and Translational Ophthalmology, Mainz, Germany
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  • Fabian Maass
    Affiliations
    Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
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  • Mathias Bähr
    Affiliations
    Department of Neurology, University Medical Center Göttingen, Göttingen, Germany

    Deutsche Forschungsgemeinschaft - German Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany
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  • Author Footnotes
    1 Contributed equally.
    Franz Grus
    Footnotes
    1 Contributed equally.
    Affiliations
    Department of Ophthalmology, University Medical Center Mainz, Experimental and Translational Ophthalmology, Mainz, Germany
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  • Author Footnotes
    1 Contributed equally.
    Paul Lingor
    Correspondence
    Corresponding author. Klinikum rechts der Isar, Klinik für Neurologie, Technische Universität München, 81675 Munich, Germany.
    Footnotes
    1 Contributed equally.
    Affiliations
    Department of Neurology, University Medical Center Göttingen, Göttingen, Germany

    Deutsche Forschungsgemeinschaft - German Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany

    Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany
    Search for articles by this author
  • Author Footnotes
    1 Contributed equally.

      Highlights

      • Tear fluid is an easily accessible biomaterial.
      • Parkinson's disease patients have reduced run lengths indicative of dry eye syndrome.
      • Disease-specific changes in tear proteome are found in Parkinson's disease patients.
      • Proteins predominantly involved in immune response and lipid metabolism are altered.

      Abstract

      Background

      The diagnosis of Parkinson's disease (PD) is still challenging and biomarkers could contribute to an improved diagnostic accuracy. Tear fluid (TF) is an easily accessible body fluid reflecting pathophysiological changes in systemic and ocular diseases and is already used as a biomarker source for several ophthalmological disorders. Here, we analyzed the TF of patients with PD and controls (CTR) to describe disease-related changes in TF and identify putative biomarkers for the diagnosis of PD.

      Methods

      Unstimulated TF samples of a pilot cohort with 36 PD patients and 18 CTR were collected via Schirmer tear test strips and then analyzed via a Bottom-up liquid chromatography electrospray ionization tandem mass spectrometry (BULCMS) workflow, followed by functional analysis encompassing protein-protein interaction as well as cellular component and pathway analysis.

      Results

      BULCMS analysis lead to the identification of 571 tear proteins (false discovery rate, FDR < 1%), whereby 31 proteins were exclusively detected in the PD group and 7 only in the CTR group. Whereas 21 proteins were significantly increased in the PD versus CTR groups, 19 proteins were significantly decreased. Core networks of proteins involved in immune response, lipid metabolism and oxidative stress were distinctly altered in PD patients.

      Conclusions

      To our best knowledge, this is the first description of TF proteome in PD patients. Tear protein level alterations suggest the contribution of different disease-related mechanisms in ocular pathology in PD and propose candidate proteins to be validated as potential biomarkers in larger cohorts.

      Keywords

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      References

        • Hughes A.J.
        • Daniel S.E.
        • Kilford L.
        • Lees A.J.
        Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.
        J. Neurol. Neurosurg. Psychiatry. 1992; 55: 181-184
        • Chahine L.M.
        • Stern M.B.
        Parkinson's disease biomarkers: where are we and where do we go next?.
        Mov. Disord. Clin. Pract. 2017; 4: 796-805
        • Lim S.-Y.
        • Lang A.E.
        The nonmotor symptoms of Parkinson's disease-An overview.
        Mov. Disord. 2010; 25: S123-S130
        • Bagheri H.
        • Berlan M.
        • Senard J.M.
        • Rascol O.
        • Montastruc J.L.
        Lacrimation in Parkinson's disease.
        Clin. Neuropharmacol. 1994; 17: 89-91
        • Söğütlü Sarı E.
        • et al.
        Tear osmolarity, break-up time and schirmer's scores in Parkinson's disease.
        Türk Oftalmoloji Dergisi. 2015; 45: 142-145
        • Kwon O.Y.
        • Kim S.H.
        • Kim J.H.
        • Kim M.H.
        • Ko M.K.
        Schrimer test in Parkinson's disease.
        J. Korean Med. Sci. 1994; 9: 239-242
        • Tamer C.
        • Melek I.M.
        • Duman T.
        • Öksüz H.
        Tear film tests in Parkinson's disease patients.
        Ophthalmology. 2005; 112: 1795.e1-1795.e8
        • Del Tredici K.
        • Hawkes C.H.
        • Ghebremedhin E.
        • Braak H.
        Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease.
        Acta Neuropathol. 2010; 119: 703-713
        • Çomoğlu S.S.
        • Güven H.
        • Acar M.
        • Öztürk G.
        • Koçer B.
        Tear levels of tumor necrosis factor-alpha in patients with Parkinson's disease.
        Neurosci. Lett. 2013; 553: 63-67
        • Kalló G.
        • et al.
        Changes in the chemical barrier composition of tears in alzheimer's disease reveal potential tear diagnostic biomarkers.
        PLoS One. 2016; 11: e0158000
        • Funke S.
        • et al.
        Analysis of the effects of preservative-free tafluprost on the tear proteome.
        Am. J. Transl. Res. 2016; 8: 4025
        • Demirci S.
        • Gunes A.
        • Koyuncuoglu H.R.
        • Tok L.
        • Tok O.
        Evaluation of Corneal Parameters in Patients with Parkinson's Disease.
        Neurological Sciences, 2016
        • Wang N.
        • Gibbons C.H.
        • Lafo J.
        • Freeman R.
        α-Synuclein in cutaneous autonomic nerves.
        Neurology. 2013; 81: 1604-1610
        • Zhou L.
        • et al.
        In-depth analysis of the human tear proteome.
        Journal of Proteomics. 2012; 75: 3877-3885
        • Singh R.
        Impression cytology of the ocular surface.
        Br. J. Ophthalmol. 2005; 89: 1655-1659
        • Soria J.
        • et al.
        The Analysis of Human Conjunctival Epithelium Proteome in Ocular Surface Diseases Using Impression Cytology and 2D-DIGE.
        Experimental Eye Research, 2017
        • Ordoñez C.
        • Navarro A.
        • Perez C.
        • Astudillo A.
        • Martínez E.
        • Tolivia J.
        Apolipoprotein D expression in substantia nigra of Parkinson disease.
        Histol. Histopathol. 2006; 21: 361-366
        • Zintzaras E.
        • Hadjigeorgiou G.M.
        Association of paraoxonase 1 gene polymorphisms with risk of Parkinson's disease: a meta-analysis.
        J. Hum. Genet. 2004; 49: 474-481
        • Rehman A.A.
        • Ahsan H.
        • Khan F.H.
        α-2-Macroglobulin: a physiological guardian.
        J. Cell. Physiol. 2013; 228: 1665-1675
        • Tang G.
        • et al.
        Alpha-2 macroglobulin I1000 V polymorphism in Chinese sporadic Alzheimer's disease and Parkinson's disease.
        Neurosci. Lett. 2002; 328: 195-197
        • Dursun E.
        • et al.
        The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease.
        J. Neuroimmunol. 2015; 283: 50-57
        • Jesse S.
        • et al.
        Differential sialylation of serpin A1 in the early diagnosis of Parkinson's disease dementia.
        PLoS One. 2012; 7: e48783
        • van Blitterswijk M.
        • et al.
        Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia.
        Amyotroph Lateral Scler Frontotemporal Degener. 2013; 14: 463-469
        • Ohashi Y.
        • et al.
        Abnormal protein profiles in tears with dry eye syndrome.
        Am. J. Ophthalmol. 2003; 136: 291-299
        • Přikrylová Vranová H.
        • et al.
        Clusterin CSF levels in differential diagnosis of neurodegenerative disorders.
        J. Neurol. Sci. Feb. 2016; 361: 117-121
        • Nichols J.J.
        • Green-Church K.B.
        Mass spectrometry-based proteomic analyses in contact lens-related dry eye.
        Cornea. Dec. 2009; 28: 1109-1117
        • Kusonmano K.
        • Netzer M.
        • Baumgartner C.
        • Dehmer M.
        • Liedl K.R.
        • Graber A.
        Effects of pooling samples on the performance of classification algorithms: a comparative study.
        ScientificWorldJournal. 2012; (2012): 278352
        • Schisterman E.F.
        • Vexler A.
        To pool or not to pool, from whether to when: applications of pooling to biospecimens subject to a limit of detection.
        Paediatr. Perinat. Epidemiol. 2008; 22: 486-496
        • Perumal N.
        • Funke S.
        • Pfeiffer N.
        • Grus F.H.
        Proteomics analysis of human tears from aqueous-deficient and evaporative dry eye patients.
        Sci. Rep. 2016; 6: 29629

      List of abbreviations

      AD
      Alzheimer's disease
      α-syn
      Alpha-synuclein
      BST
      Basic secretion test
      BULCMS
      Bottom-up liquid chromatography electrospray ionization tandem mass spectrometry
      CSF
      Cerebrospinal fluid
      CTR
      Controls
      DES
      Dry eye syndrome
      FDR
      False discovery rate
      GO
      Gene ontology
      mHY
      Modified Hoehn and Yahr (Scale)
      MS
      Mass spectrometry
      PD
      Parkinson's disease
      PD-NMS
      Parkinson's Disease-Non-Motor Symptoms (Scale)
      PPI
      Protein-protein interaction
      REM
      Rapid eye movement
      TF
      Tear fluid
      TPC
      Total protein concentration
      UPDRS
      Unified Parkinson's disease rating scale