Abstract
The deregulation of several microRNAs (miRNAs) has been associated with neurodegenerative processes, including Parkinson’s disease (PD). Our aim was to characterize the level of miRNAs in the substantia nigra (SN) of PD patients and healthy donors. This is an important issue to characterize new putative markers and therapeutic targets for PD. RNA was extracted from the SN of postmortem PD (n = 8) and healthy (n = 4) subjects, and the level of 733 human miRNAs was assayed with TaqMan low-density arrays (TLDAs). Overall, there was a miRNA downregulation in the SN of patients. The mean level of 11 miRNAs was significantly different (p < 0.05) between patients and controls, with 10 downregulated among the patients. MiR-198, -135b, -485-5p, and -548d were the best candidates and were quantified with individual TaqMan assays in the 12 samples. MiR-135b showed the most significant difference between patients and healthy donors. The bioinformatic analysis suggested that this miRNA could bind to genes implicated in several neurodegenerative pathways.
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Alvarez-Erviti L, Seow Y, Schapira AH, Rodriguez-Oroz MC, Obeso JA, Cooper JM (2013) Influence of microRNA deregulation on chaperone-mediated autophagy and alpha-synuclein pathology in Parkinson’s disease. Cell Death Dis 4:e545
Bekris LM, Lutz F, Montine TJ et al (2013) MicroRNA in Alzheimer’s disease: an exploratory study in brain, cerebrospinal fluid and plasma. Biomarkers 18:455–466
Botta-Orfila T, Morato X, Compta Y et al (2014) Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson’s disease. J Neurosci Res 92:1071–1077
Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134
Cardo LF, Coto E, de Mena L et al (2013) Profile of microRNAs in the plasma of Parkinson’s disease patients and healthy controls. J Neurol 260:1420–1422
Cardo LF, Coto E, de Mena L et al (2014a) Alpha-synuclein transcript isoforms in three different brain regions from Parkinson’s disease and healthy subjects in relation to the SNCA rs356165/rs11931074 polymorphisms. Neurosci Lett 562:45–49
Cardo LF, Coto E, Ribacoba R et al (2014b) The screening of the 3′UTR sequence of LRRK2 identified an association between the rs66737902 polymorphism and Parkinson’s disease. J Hum Genet 59:346–348
Chatterjee P, Bhattacharyya M, Bandyopadhyay S, Roy D (2014) Studying the system-level involvement of microRNAs in Parkinson’s disease. PLoS One 9:e93751
Cho HJ, Liu G, Jin SM et al (2012) MicroRNA-205 regulates the expression of Parkinson’s disease-related leucine-rich repeat kinase 2 protein. Hum Mol Genet 22:608–620
De Mena L, Cardo LF, Coto E, Alvarez V (2013) No differential DNA methylation of PARK2 in brain of Parkinson’s disease patients and healthy controls. Mov Disord 28:2032–2033
Doxakis E (2010) Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J Biol Chem 285:12726–12734
Eacker SM, Dawson TM, Dawson VL (2009) Understanding microRNAs in neurodegeneration. Nat Rev Neurosci 10:837–841
Faghihi MA, Zhang M, Huang J et al (2010) Evidence for natural antisense transcript-mediated inhibition of microRNA function. Genome Biol 11:R56
Gehrke S, Imai Y, Sokol N, Lu B (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466:637–641
Gilad S, Meiri E, Yogev Y et al (2008) Serum microRNAs are promising novel biomarkers. PLoS One 3:e3148
Hansen T, Olsen L, Lindow M et al (2007) Brain expressed microRNAs implicated in schizophrenia etiology. PLoS One 2:e873
Jung M, Schaefer A, Steiner I et al (2010) Robust microRNA stability in degraded RNA preparations from human tissue and cell samples. Clin Chem 56:998–1006
Junn E, Lee KW, Jeong BS, Chan TW, Im JY, Mouradian MM (2009) Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci U S A 106:13052–13057
Khoo SK, Petillo D, Kang UJ et al (2012) Plasma-based circulating microRNA biomarkers for Parkinson’s disease. J Park Dis 2:321–331
Kim J, Inoue K, Ishii J et al (2007) A MicroRNA feedback circuit in midbrain dopamine neurons. Science 317:1220–1224
Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs. Science 294:853–858
Lai CY, Yu SL, Hsieh MH et al (2011) MicroRNA expression aberration as potential peripheral blood biomarkers for schizophrenia. PLoS One 6:e21635
Liao XY, Wang WW, Yang ZH et al (2013) Microarray analysis of transcriptome of medulla identifies potential biomarkers for Parkinson’s disease. Int J Genom 2013:606919
Long JM, Ray B, Lahiri DK (2014) MicroRNA-339-5p down-regulates protein expression of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J Biol Chem 289:5184–5198
Maciotta S, Meregalli M, Torrente Y (2013) The involvement of microRNAs in neurodegenerative diseases. Front Cell Neurosci 7:e265
Martins M, Rosa A, Guedes LC et al (2011) Convergence of miRNA expression profiling, alpha-synuclein interaction and GWAS in Parkinson’s disease. PLoS One 6:e25443
Minones-Moyano E, Porta S, Escaramis G et al (2011) MicroRNA profiling of Parkinson’s disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet 20:3067–3078
Minones-Moyano E, Friedlander MR, Pallares J et al (2013) Upregulation of a small vault RNA (svtRNA2-1a) is an early event in Parkinson disease and induces neuronal dysfunction. RNA Biol 10:1093–1106
Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31:763–780
Olsen L, Klausen M, Helboe L, Nielsen FC, Werge T (2009) MicroRNAs show mutually exclusive expression patterns in the brain of adult male rats. PLoS One 4:e7225
Palacín M, Reguero JR, Martín M et al (2011) Profile of microRNAs differentially produced in hearts from patients with hypertrophic cardiomyopathy and sarcomeric mutations. Clin Chem 57:1614–1616
Prior C, Perez-Gracia JL, Garcia-Donas J et al (2014) Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma. PLoS One 9:e86263
Sonntag KC (2010) MicroRNAs and deregulated gene expression networks in neurodegeneration. Brain Res 1338:48–57
Soreq L, Salomonis N, Bronstein M et al (2013) Small RNA sequencing-microarray analyses in Parkinson leukocytes reveal deep brain stimulation-induced splicing changes that classify brain region transcriptomes. Front Mol Neurosci 6:e10
Vallelunga A, Ragusa M, Di Mauro S et al (2014) Identification of circulating microRNAs for the differential diagnosis of Parkinson’s disease and multiple system atrophy. Front Cell Neurosci 8:156
Wang G, van der Walt JM, Mayhew G et al (2008) Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet 82:283–289
Zahm AM, Thayu M, Hand NJ, Horner A, Leonard MB, Friedman JR (2011) Circulating microRNA is a biomarker of pediatric Crohn disease. J Pediatr Gastroenterol Nutr 53:26–33
Acknowledgments
We thank the London Neurodegenerative Diseases Brain Bank (LNDBB) for supplying all postmortem brain samples. We thank the “Fundacion Parkinson Asturias” and “Obra Social Cajastur” for their support. This work was supported by grants from the Spanish “Fondo de Investigaciones Sanitarias-Fondos FEDER” European Union (FIS 11/0093). LFC holds a predoctoral fellowship from FICYT-Principado de Asturias.
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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Authors’ Contribution
All the authors contributed to this work by recruiting the patients and obtaining the clinical and anthropometric data (RR, MM, GM, and ES) or performing the laboratory work (LFC, EC, and VA). All authors have read and approved the submission of this manuscript.
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Cardo, L.F., Coto, E., Ribacoba, R. et al. MiRNA Profile in the Substantia Nigra of Parkinson’s Disease and Healthy Subjects. J Mol Neurosci 54, 830–836 (2014). https://doi.org/10.1007/s12031-014-0428-y
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DOI: https://doi.org/10.1007/s12031-014-0428-y