Identification of distinct blood-based biomarkers in early stage of Parkinson’s disease
Parkinson’s disease (PD) is a slowly progressive geriatric disease, which can be one of the leading causes of serious socioeconomic burden in the aging society. Clinical trials suggest that prompt treatment of early-stage Parkinson’s disease (EPD) may slow down the disease progress and have a better response. Therefore, conducting proteomics study to identify biomarkers for the diagnosis and disease-modifying therapies of EPD is vital. We aimed at identifying distinct protein autoantibody biomarkers of EPD by using the database of GSE62283 based on the platform GPL13669 downloaded from Gene Expression Omnibus database. Differentially expressed proteins (DEPs) between the EPD group (n = 103) and the normal control (NC) group (n = 111) were identified by protein-specific t test. Cluster analysis of DEPs was conducted by protein–protein interaction network to detect hub proteins. The hub proteins were then evaluated to determine the distinct biomarkers by principal component analysis, as well as functional and pathway enrichment analysis. Their biological functions were confirmed by gene ontology functional (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment (KEGG). Two biomarkers, mitochondrial ribosome recycling factor (MRRF) and ribosomal protein S18 (RPS18), distinguished the EPD samples from the NC samples, and they were regarded as high-confidence distinct protein autoantibody biomarkers of EPD. The most significant GO function was protein serine/threonine kinase activity (GO: 0004674) and most of DEPs were enriched in ATP binding in molecular function category (GO: 0005524). These results may help in establishing the prompt and accurate diagnosis of EPD and may also contribute to develop mechanism-based treatments.
KeywordsEarly-stage Parkinson’s disease Blood-based biomarker Functional analysis Protein-protein interaction
Early-stage Parkinson’s disease
Differentially expressed proteins
Kyoto encyclopedia of genes and genomes
Principal component analysis
This work was supported by the National Key R&D Program of China (grant number 2016YFC1306000).
Compliance with ethical standards
The original study  is approved by Rowan-Stratford Institutional Review Board.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Lin X, Cook TJ, Zabetian CP, Leverenz JB, Peskind ER, Hu SC, Cain KC, Pan C, Edgar JS, Goodlett DR, Racette BA, Checkoway H, Montine TJ, Shi M, Zhang J (2012) DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease. Sci Rep 2:954. https://doi.org/10.1038/srep00954 CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68(5):384–386. https://doi.org/10.1212/01.wnl.0000247740.47667.03 CrossRefGoogle Scholar
- 6.Zhao YJ, Wee HL, Au WL, Seah SH, Luo N, Li SC, Tan LC (2011) Selegiline use is associated with a slower progression in early Parkinson’s disease as evaluated by Hoehn and Yahr stage transition times. Parkinsonism Relat Disord 17(3):194–197. https://doi.org/10.1016/j.parkreldis.2010.11.010 CrossRefPubMedGoogle Scholar
- 9.Hoehn M, Yahr M (2011) Parkinsonism: Onset, progression, and mortality. Neurology 77(9):874–874. https://doi.org/10.1212/01.wnl.0000405146.06300.91 CrossRefGoogle Scholar
- 16.Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, Sabbagh MN, Sue LI, Jacobson SA, Belden CM, Dugger BN (2014) Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology 83(5):406–412. https://doi.org/10.1212/WNL.0000000000000641 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Sulzer D, Cassidy C, Horga G, Kang UJ, Fahn S, Casella L, Pezzoli G, Langley J, Hu XP, Zucca FA, Isaias IU, Zecca L (2018) Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease. NPJ Parkinson's disease 4:11. https://doi.org/10.1038/s41531-018-0047-3 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.DeMarshall CA, Han M, Nagele EP, Sarkar A, Acharya NK, Godsey G, Goldwaser EL, Kosciuk M, Thayasivam U, Belinka B, Nagele RG, Parkinson’s Study Group I (2015) Potential utility of autoantibodies as blood-based biomarkers for early detection and diagnosis of Parkinson’s disease. Immunol Lett 168(1):80–88. https://doi.org/10.1016/j.imlet.2015.09.010 CrossRefPubMedGoogle Scholar
- 24.Reetz K, Lencer R, Steinlechner S, Gaser C, Hagenah J, Buchel C, Petersen D, Kock N, Djarmati A, Siebner HR, Klein C, Binkofski F (2008) Limbic and frontal cortical degeneration is associated with psychiatric symptoms in PINK1 mutation carriers. Biol Psychiatry 64(3):241–247. https://doi.org/10.1016/j.biopsych.2007.12.010 CrossRefPubMedGoogle Scholar
- 25.van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P (2001) Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Human Genet 69(3):629–634. https://doi.org/10.1086/322996 CrossRefGoogle Scholar
- 26.Huang DW, Sherman BT, Tan Q, Collins JR, Alvord WG, Roayaei J, Stephens R, Baseler MW, Lane HC, Lempicki RA (2007) The DAVID gene functional classification tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol 8(9):R183. https://doi.org/10.1186/gb-2007-8-9-r183 CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Sim CH, Lio DS, Mok SS, Masters CL, Hill AF, Culvenor JG, Cheng HC (2006) C-terminal truncation and Parkinson’s disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Human Mol Genet 15(21):3251–3262. https://doi.org/10.1093/hmg/ddl398 CrossRefGoogle Scholar
- 35.Inamdar AA, Masurekar P, Hossain M, Richardson JR, Bennett JW (2014) Signaling pathways involved in 1-octen-3-ol-mediated neurotoxicity in Drosophila melanogaster: implication in Parkinson’s disease. Neurotox Res 25(2):183–191. https://doi.org/10.1007/s12640-013-9418-z CrossRefPubMedPubMedCentralGoogle Scholar
- 37.EMBL-EBI Quick GO (2009) https://wwwe.biacuk/QuickGO/. Accessed 3 Apr 2018
- 43.Voshavar C, Shah M, Xu L, Dutta AK (2015) Assessment of protective role of multifunctional dopamine agonist D-512 against oxidative stress produced by depletion of glutathione in PC12 cells: implication in neuroprotective therapy for Parkinson’s disease. Neurotox Res 28(4):302–318. https://doi.org/10.1007/s12640-015-9548-6 CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Jiang D, Shi S, Zhang L, Liu L, Ding B, Zhao B, Yagnik G, Zhou F (2013) Inhibition of the Fe(III)-catalyzed dopamine oxidation by ATP and its relevance to oxidative stress in Parkinson’s disease. ACS Chem Neurosci 4(9):1305–1313. https://doi.org/10.1021/cn400105d CrossRefPubMedPubMedCentralGoogle Scholar
- 51.Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science (New York, NY) 299(5604):256–259. https://doi.org/10.1126/science.1077209 CrossRefGoogle Scholar