A molecular signature in blood identifies early Parkinson’s disease

Molecular Neurodegeneration

Silvia A Mandel⁷  Moussa BH Youdim³  Yulia Bashenko⁷  Judith Aharon-Peretz²  Christian Jacob⁵  Peter Riederer⁵  Edna Grünblatt⁵  Daniela Frosini⁶  Roberto Ceravolo⁶  Ubaldo Bonuccelli⁶  Evgenya Dobronevsky⁴  Jose M Rabey¹  Leonid Molochnikov¹ 

[1] Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;Department of Neurology, Rambam Medical Center, Haifa, Israel;Department of Biology, Yonsei Central University, Seoul, Republic of Korea;Asaf HaRofeh Medical Center, Department of Neurology, Zerifin, Israel;Department of Psychiatry, Psychosomatic and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany;Department of Neuroscience, University of Pisa, Pisa, Italy;Technion-Faculty of Medicine, Eve Topf Center for Neurodegenerative Diseases Research, Department of Molecular Pharmacology, P.O.B. 9697 31096, Haifa, Israel

关键词: Early diagnosis;    Heat shock protein Hsc-70;    SKP1;    SCF;    E3 ubiquitin ligase;    CSF Biomarkers;    Blood Biomarker;    Sporadic Parkinson’s disease;    Alzheimer’s disease;   

Others  :  863811
DOI  :  10.1186/1750-1326-7-26

 received in 2012-02-23, accepted in 2012-05-31,  发布年份 2012

【 摘 要 】

Background

The search for biomarkers in Parkinson’s disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD.

Results

The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60–0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08–1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75–0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60–0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14–1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96.

The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer’s disease (n = 29).

Conclusions

The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.

【 授权许可】

   
2012 Molochnikov et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 4.

【 参考文献 】

• [1]Hughes AJ, Daniel SE, Kilford L, Lees AJ: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992, 55:181-184.
• [2]Fahn S, Elton R, UPDRS Development Committee: Unified Parkinson’s disease rating scale. In In Recent Developments in Parkinson’s Disease. Volume 2. Edited by Fahn S, Marsden CD, Goldstein M. New York: Macmillan; 1987:153-167.
• [3]Rabey JM, Bass H, Bonuccelli U, Brooks D, Klotz P, Korczyn AD, Kraus P, Martinez-Martin P, Morrish P, Van Sauten W, Van Hilten B: Evaluation of the Short Parkinson’s Evaluation Scale: a new friendly scale for the evaluation of Parkinson’s disease in clinical drug trials. Clin Neuropharmacol 1997, 20:322-337.
• [4]Marinus J, Visser M, Stiggelbout AM, Rabey JM, Martinez-Martin P, Bonuccelli U, Kraus PH, van Hilten JJ: A short scale for the assessment of motor impairments and disabilities in Parkinson’s disease: the SPES/SCOPA. J Neurol Neurosurg Psychiatry 2004, 75:388-395.
• [5]Hoehn MM, Yahr MD: Parkinsonism: onset, progression and mortality. Neurology 1967, 17:427-442.
• [6]Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ: What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology 1992, 42:1142-1146.
• [7]Yekhlef F, Ballan G, Macia F, Delmer O, Sourgen C, Tison F: Routine MRI for the differential diagnosis of Parkinson’s disease, MSA, PSP, and CBD. J Neural Transm 2003, 110:151-169.
• [8]Davie CA, Wenning GK, Barker GJ, Tofts PS, Kendall BE, Quinn N, McDonald WI, Marsden CD, Miller DH: Differentiation of multiple system atrophy from idiopathic Parkinson’s disease using proton magnetic resonance spectroscopy. Ann Neurol 1995, 37:204-210.
• [9]Barbiroli B, Martinelli P, Patuelli A, Lodi R, Iotti S, Cortelli P, Montagna P: Phosphorus magnetic resonance spectroscopy in multiple system atrophy and Parkinson’s disease. Mov Disord 1999, 14:430-435.
• [10]Jankovic J, Rajput AH, McDermott MP, Perl DP: The evolution of diagnosis in early Parkinson disease. Parkinson Study Group. Arch Neurol 2000, 57:369-372.
• [11]Grunblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P, Youdim MB: Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm 2004, 111:1543-1573.
• [12]Hauser MA, Li YJ, Xu H, Noureddine MA, Shao YS, Gullans SR, Scherzer CR, Jensen RV, McLaurin AC, Gibson JR, et al.: Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. Arch Neurol 2005, 62:917-921.
• [13]Miller RM, Kiser GL, Kaysser-Kranich TM, Lockner RJ, Palaniappan C, Federoff HJ: Robust dysregulation of gene expression in substantia nigra and striatum in Parkinson’s disease. Neurobiol Dis 2006, 21:305-313.
• [14]Moran LB, Duke DC, Deprez M, Dexter DT, Pearce RK, Graeber MB: Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson’s disease. Neurogenetics 2006, 7:1-11.
• [15]Zhang Y, James M, Middleton FA, Davis RL: Transcriptional analysis of multiple brain regions in Parkinson’s disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet 2005, 137:5-16.
• [16]Gasser T: Mendelian forms of Parkinson’s disease. Biochim Biophys Acta 2009, 1792:587-596.
• [17]Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, et al.: Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 2002, 416:703-709.
• [18]Feldman RM, Correll CC, Kaplan KB, Deshaies RJ: A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 1997, 91:221-230.
• [19]Murata S, Chiba T, Tanaka K: CHIP: a quality-control E3 ligase collaborating with molecular chaperones. Int J Biochem Cell Biol 2003, 35:572-578.
• [20]Eller M, Williams DR: Biological fluid biomarkers in neurodegenerative parkinsonism. Nat Rev Neurol 2009, 5:561-570.
• [21]Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Leverenz JB, Baird G, et al.: DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain 2010, 133:713-726.
• [22]Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, Sixel-Doring F, Trenkwalder C, Schlossmacher MG: alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 2011, 10:230-240.
• [23]Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T, Ishigami N, Tamaoka A, Nakagawa M, El-Agnaf OM: Detection of elevated levels of {alpha}-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 2010, 75:1766-1770.
• [24]Weisskopf MG, O’Reilly E, Chen H, Schwarzschild MA, Ascherio A: Plasma urate and risk of Parkinson’s disease. Am J Epidemiol 2007, 166:561-567.
• [25]Davis JW, Grandinetti A, Waslien CI, Ross GW, White LR, Morens DM: Observations on serum uric acid levels and the risk of idiopathic Parkinson’s disease. Am J Epidemiol 1996, 144:480-484.
• [26]Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, Shoulson I, Ascherio A, Hyson C, Gorbold E, et al.: Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol 2008, 65:716-723.
• [27]Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, et al.: Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci U S A 2007, 104:955-960.
• [28]Sullivan PF, Fan C, Perou CM: Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet 2006, 141B:261-268.
• [29]Domenici E, Wille DR, Tozzi F, Prokopenko I, Miller S, McKeown A, Brittain C, Rujescu D, Giegling I, Turck CW, et al.: Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case–control collections. PLoS One 2010, 5:e9166.
• [30]Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, et al.: PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med 2010, 2:52ra73.
• [31]Shehadeh LA, Yu K, Wang L, Guevara A, Singer C, Vance J, Papapetropoulos S: SRRM2, a potential blood biomarker revealing high alternative splicing in Parkinson’s disease. PLoS One 2010, 5:e9104.
• [32]Aasly JO, Shi M, Sossi V, Stewart T, Johansen KK, Wszolek ZK, Uitti RJ, Hasegawa K, Yokoyama T, Zabetian CP, et al.: Cerebrospinal fluid amyloid beta and tau in LRRK2 mutation carriers. Neurology 2012, 78:55-61.
• [33]Liew CC, Ma J, Tang HC, Zheng R, Dempsey AA: The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. J Lab Clin Med 2006, 147:126-132.
• [34]Mardh G, Vallee BL: Human class I alcohol dehydrogenases catalyze the interconversion of alcohols and aldehydes in the metabolism of dopamine. Biochemistry 1986, 25:7279-7282.
• [35]Hjelle JJ, Petersen DR: Hepatic aldehyde dehydrogenases and lipid peroxidation. Pharmacol Biochem Behav 1983, 18(Suppl 1):155-160.
• [36]de Pril R, Fischer DF, Roos RA, van Leeuwen FW: Ubiquitin-conjugating enzyme E2-25 K increases aggregate formation and cell death in polyglutamine diseases. Mol Cell Neurosci 2007, 34:10-19.
• [37]Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, et al.: C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001, 107:43-54.
• [38]Fishman-Jacob T, Reznichenko L, Youdim MB, Mandel SA: A sporadic parkinson’s disease model via silencing of the ubiquitin-proteasome/E3-ligase component, SKP1A. J Biol Chem 2009, 284(47):32835-32845.
• [39]Galter D, Buervenich S, Carmine A, Anvret M, Olson L: ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson’s disease and in the ventral tegmental area in schizophrenia. Neurobiol Dis 2003, 14:637-647.
• [40]Mandel SA, Fishman T, Youdim MB: Gene and protein signatures in sporadic Parkinson’s disease and a novel genetic model of PD. Parkinsonism Relat Disord 2007, 13(Suppl 3):S242-S247.
• [41]Grunblatt E, Zehetmayer S, Jacob CP, Muller T, Jost WH, Riederer P: Pilot study: peripheral biomarkers for diagnosing sporadic Parkinson’s disease. J Neural Transm 2010, 117(12):1387-1393.
• [42]Shi M, Bradner J, Hancock AM, Chung KA, Quinn JF, Peskind ER, Galasko D, Jankovic J, Zabetian CP, Kim HM, et al.: Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression. Ann Neurol 2010, 69:570-580.
• [43]McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984, 34:939-944.
• [44]Spinsanti G, Zannolli R, Panti C, et al.: Quantitative Real-Time PCR detection of TRPV1-4 gene expression in human leukocytes from healthy and hyposensitive subjects. Mol Pain 2008, 4:51. BioMed Central Full Text
• [45]Vandesompele J, De Preter K, Pattyn F, et al.: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002, 3(7):RESEARCH0034.