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Low-variance RNAs identify Parkinson's disease molecular signature in blood.
Mov Disord. 2015 May; 30(6):813-21.MD

Abstract

The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection.

Authors+Show Affiliations

Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Department of Computer Science, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.Department of Computer Science, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.Department of Computer Science, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.Department of Neurology, Mount Sinai Beth Israel, New York, New York, USA.Department of Neurology, Mount Sinai Beth Israel, New York, New York, USA.Department of Neurology, Mount Sinai Beth Israel, New York, New York, USA.Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25786808

Citation

Chikina, Maria D., et al. "Low-variance RNAs Identify Parkinson's Disease Molecular Signature in Blood." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 30, no. 6, 2015, pp. 813-21.
Chikina MD, Gerald CP, Li X, et al. Low-variance RNAs identify Parkinson's disease molecular signature in blood. Mov Disord. 2015;30(6):813-21.
Chikina, M. D., Gerald, C. P., Li, X., Ge, Y., Pincas, H., Nair, V. D., Wong, A. K., Krishnan, A., Troyanskaya, O. G., Raymond, D., Saunders-Pullman, R., Bressman, S. B., Yue, Z., & Sealfon, S. C. (2015). Low-variance RNAs identify Parkinson's disease molecular signature in blood. Movement Disorders : Official Journal of the Movement Disorder Society, 30(6), 813-21. https://doi.org/10.1002/mds.26205
Chikina MD, et al. Low-variance RNAs Identify Parkinson's Disease Molecular Signature in Blood. Mov Disord. 2015;30(6):813-21. PubMed PMID: 25786808.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Low-variance RNAs identify Parkinson's disease molecular signature in blood. AU - Chikina,Maria D, AU - Gerald,Christophe P, AU - Li,Xianting, AU - Ge,Yongchao, AU - Pincas,Hanna, AU - Nair,Venugopalan D, AU - Wong,Aaron K, AU - Krishnan,Arjun, AU - Troyanskaya,Olga G, AU - Raymond,Deborah, AU - Saunders-Pullman,Rachel, AU - Bressman,Susan B, AU - Yue,Zhenyu, AU - Sealfon,Stuart C, Y1 - 2015/03/18/ PY - 2014/06/04/received PY - 2015/01/23/revised PY - 2015/02/09/accepted PY - 2015/3/20/entrez PY - 2015/3/20/pubmed PY - 2016/4/8/medline KW - LRRK2 mutation KW - Parkinson's disease KW - blood KW - functional genomics KW - low coefficient of variation markers SP - 813 EP - 21 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov Disord VL - 30 IS - 6 N2 - The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection. SN - 1531-8257 UR - https://www.unboundmedicine.com/medline/citation/25786808/Low_variance_RNAs_identify_Parkinson's_disease_molecular_signature_in_blood_ L2 - https://doi.org/10.1002/mds.26205 DB - PRIME DP - Unbound Medicine ER -