To complement the molecular pathways contributing to Parkinson’s disease (PD) and identify potential biomarkers, gene expression profiles of two regions of the medulla were compared between PD patients and control. GSE19587 containing two groups of gene expression profiles [6 dorsal motor nucleus of the vagus (DMNV) samples from PD patients and 5 from controls, 6 inferior olivary nucleus (ION) samples from PD patients and 5 from controls] was downloaded from Gene Expression Omnibus. As a result, a total of 1569 and 1647 differentially expressed genes (DEGs) were, respectively, screened in DMNV and ION with limma package of R. The functional enrichment analysis by DAVID server (the Database for Annotation, Visualization and Integrated Discovery) indicated that the above DEGs may be involved in the following processes, such as regulation of cell proliferation, positive regulation of macromolecule metabolic process, and regulation of apoptosis. Further analysis showed that there were 365 common DEGs presented in both regions (DMNV and ION), which may be further regulated by eight clusters of microRNAs retrieved with WebGestalt. The genes in the common DEGs-miRNAs regulatory network were enriched in regulation of apoptosis process via DAVID analysis. These findings could not only advance the understandings about the pathogenesis of PD, but also suggest potential biomarkers for this disease. 1. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative disorder in human, which is characterized by progressive death of dopamine-generating cells in the substantia nigra and accumulation of intraneuronal Lewy bodies containing misfolded fibrillar α-synuclein (SNCA), which eventually results in progressive movement disorders, including shaking, rigidity, bradykinesia, and gait disturbance [1]. Epidemiologic studies have identified environmental factors such as trauma [2] and pesticide exposure [3, 4] as risk factors for PD, while the increasing evidence demonstrates that genetic factors play significant roles in PD. Several genes have been linked to PD, such as SNCA, leucine-rich repeat kinase 2 (LRRK2), parkin (PARK2), PTEN-induced kinase 1 (PINK1), and DJ-1 (PARK7) [5, 6]. In addition, as an important regulator at posttranscriptional level, several miRNAs have been discovered to be involved in PD pathogenesis via regulating PD-associated gene expression. For example, miR-7 and miR-153 are recently described to regulate endogenous synuclein levels; inhibition of α-synuclein expression by miR-7 protects against oxidative stress-mediated cell
References
[1]
S. Phani, J. D. Loike, and S. Przedborski, “Neurodegeneration and inflammation in Parkinson's disease,” Parkinsonism and Related Disorders, vol. 18, supplement 1, pp. S207–S209, 2012.
[2]
J. P. Hubble, T. Cao, R. E. S. Hassanein, J. S. Neuberger, and W. C. Koller, “Risk factors for Parkinson's disease,” Neurology, vol. 43, no. 9, pp. 1693–1697, 1993.
[3]
A. Ascherio, H. Chen, M. G. Weisskopf et al., “Pesticide exposure and risk for Parkinson's disease,” Annals of Neurology, vol. 60, no. 2, pp. 197–203, 2006.
[4]
J. M. Gorell, C. C. Johnson, B. A. Rybicki, E. L. Peterson, and R. J. Richardson, “The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living,” Neurology, vol. 50, no. 5, pp. 1346–1350, 1998.
[5]
S. T. Camargos, L. O. Dornas, P. Momeni et al., “Familial Parkinsonism and early onset Parkinson's disease in a Brazilian movement disorders clinic: phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations,” Movement Disorders, vol. 24, no. 5, pp. 662–666, 2009.
[6]
C. Y.-C. Chen, “Mechanism of BAG1 repair on Parkinson’s disease-linked DJ1 mutation,” Journal of Biomolecular Structure and Dynamics, vol. 30, no. 1, pp. 1–12, 2012.
[7]
E. Junn, K.-W. Lee, S. J. Byeong, T. W. Chan, J.-Y. Im, and M. M. Mouradian, “Repression of α-synuclein expression and toxicity by microRNA-7,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 13052–13057, 2009.
[8]
E. Doxakis, “Post-transcriptional regulation of α-synuclein expression by mir-7 and mir-153,” Journal of Biological Chemistry, vol. 285, no. 17, pp. 12726–12734, 2010.
[9]
E. Filatova, “MicroRNAs: possible role in pathogenesis of Parkinson’s disease,” Biochemistry, vol. 77, no. 8, pp. 813–819, 2012.
[10]
H. Braak, K. Del Tredici, U. Rüb, R. A. I. de Vos, E. N. H. Jansen Steur, and E. Braak, “Staging of brain pathology related to sporadic Parkinson's disease,” Neurobiology of Aging, vol. 24, no. 2, pp. 197–211, 2003.
[11]
T. Jubault, S. M. Brambati, C. Degroot et al., “Regional brain stem atrophy in idiopathic Parkinson's disease detected by anatomical MRI,” PloS one, vol. 4, no. 12, Article ID e8247, 2009.
[12]
G. A. Korbel, G. Lalic, and M. D. Shair, “Reaction microarrays: a method for rapidly determining the enantiomeric excess of thousands of samples [16],” Journal of the American Chemical Society, vol. 123, no. 2, pp. 361–362, 2001.
[13]
S. Mandel, E. Grünblatt, G. Maor, and M. B. H. Youdim, “Early and late gene changes in MPTP mice model of Parkinson's disease employing cDNA microarray,” Neurochemical Research, vol. 27, no. 10, pp. 1231–1243, 2002.
[14]
F. Simunovic, M. Yi, Y. Wang et al., “Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson's disease pathology,” Brain, vol. 132, no. 7, pp. 1795–1809, 2009.
[15]
N. M. Lewandowski, S. Ju, M. Verbitsky et al., “Polyamine pathway contributes to the pathogenesis of Parkinson disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 39, pp. 16970–16975, 2010.
[16]
R. Edgar, M. Domrachev, and A. E. Lash, “Gene Expression Omnibus: NCBI gene expression and hybridization array data repository,” Nucleic Acids Research, vol. 30, no. 1, pp. 207–210, 2002.
[17]
O. Troyanskaya, M. Cantor, G. Sherlock et al., “Missing value estimation methods for DNA microarrays,” Bioinformatics, vol. 17, no. 6, pp. 520–525, 2001.
[18]
A. Fujita, J. R. Sato, L. de Oliveira Rodrigues, C. E. Ferreira, and M. C. Sogayar, “Evaluating different methods of microarray data normalization,” BMC Bioinformatics, vol. 7, no. 1, p. 469, 2006.
[19]
G. K. Smyth, Limma: Linear Models For Microarray Data, in BioinFormatics and Computational Biology Solutions Using R and Bioconductor, Springer, 2005.
[20]
D. W. Huang, B. T. Sherman, and R. A. Lempicki, “Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources,” Nature Protocols, vol. 4, no. 1, pp. 44–57, 2009.
[21]
B. Zhang, S. Kirov, and J. Snoddy, “WebGestalt: an integrated system for exploring gene sets in various biological contexts,” Nucleic Acids Research, vol. 33, supplement 2, pp. W741–W748, 2005.
[22]
D. Duncan, N. Prodduturi, and B. Zhang, “WebGestalt2: an updated and expanded version of the web-based gene set analysis toolkit,” BMC Bioinformatics, vol. 11, supplement 4, p. 10, 2010.
[23]
Y. Benjamini and Y. Hochberg, “Controlling the false discovery rate: a practical and powerful approach to multiple testing,” Journal of the Royal Statistical Society B, vol. 57, pp. 289–300, 1995.
[24]
R. E. Burke and N. Kholodilov, “Programmed cell death: does it play a role in Parkinson's disease?” Annals of Neurology, vol. 44, supplement 3, pp. S126–S133, 1998.
[25]
M. P. Mattson, “Apoptosis in neurodegenerative disorders,” Nature Reviews Molecular Cell Biology, vol. 1, no. 2, pp. 120–130, 2000.
[26]
X. Cui, J. J. McGrath, T. H. J. Burne, A. Mackay-Sim, and D. W. Eyles, “Maternal vitamin D depletion alters neurogenesis in the developing rat brain,” International Journal of Developmental Neuroscience, vol. 25, no. 4, pp. 227–232, 2007.
[27]
H. L. Newmark and J. Newmark, “Vitamin D and Parkinson's disease—a hypothesis,” Movement Disorders, vol. 22, no. 4, pp. 461–468, 2007.
[28]
J. P. Kesby, X. Cui, P. Ko, J. J. McGrath, T. H. J. Burne, and D. W. Eyles, “Developmental vitamin D deficiency alters dopamine turnover in neonatal rat forebrain,” Neuroscience Letters, vol. 461, no. 2, pp. 155–158, 2009.
[29]
E. Garcion, N. Wion-Barbot, C. N. Montero-Menei, F. Berger, and D. Wion, “New clues about vitamin D functions in the nervous system,” Trends in Endocrinology and Metabolism, vol. 13, no. 3, pp. 100–105, 2002.
[30]
M. W. Butler, A. Burt, T. L. Edwards et al., “Vitamin D Receptor Gene as a Candidate Gene for Parkinson Disease,” Annals of Human Genetics, vol. 75, no. 2, pp. 201–210, 2011.
[31]
Z. Lv, “Association study between vitamin d receptor gene polymorphisms and patients with Parkinson disease in Chinese Han population,” International Journal of Neuroscience, vol. 123, no. 1, pp. 60–64, 2012.
[32]
J.-S. Kim, Y.-I. Kim, C. Song et al., “Association of vitamin D receptor gene polymorphism and Parkinson's disease in Koreans,” Journal of Korean Medical Science, vol. 20, no. 3, pp. 495–498, 2005.
[33]
S. T. Lim, M. Airavaara, and B. K. Harvey, “Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS,” Pharmacological Research, vol. 61, no. 1, pp. 14–26, 2010.
[34]
J. R. Evans and R. A. Barker, “Neurotrophic factors as a therapeutic target for Parkinson's disease,” Expert Opinion on Therapeutic Targets, vol. 12, no. 4, pp. 437–447, 2008.
[35]
T. Kano, Y. Suzuki, M. Shibuya, K. Kiuchi, and M. Hagiwara, “Cocaine-induced CREB phosphorylation and c-Fos expression are suppressed in Parkinsonism model mice,” NeuroReport, vol. 6, no. 16, pp. 2197–2200, 1995.
[36]
A. D. Ebert, A. J. Beres, A. E. Barber, and C. N. Svendsen, “Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease,” Experimental Neurology, vol. 209, no. 1, pp. 213–223, 2008.
[37]
R. Roshan, T. Ghosh, V. Scaria, and B. Pillai, “MicroRNAs: novel therapeutic targets in neurodegenerative diseases,” Drug Discovery Today, vol. 14, no. 23-24, pp. 1123–1129, 2009.
[38]
J. Xiong, “Emerging roles of microRNA-22 in human disease and normal physiology,” Current Molecular Medicine, vol. 12, no. 3, pp. 247–258, 2012.
[39]
R. Margis, R. Margis, and C. R. Rieder, “Identification of blood microRNAs associated to Parkinsonós disease,” Journal of Biotechnology, vol. 152, no. 3, pp. 96–101, 2011.
[40]
S. Altamura and M. U. Muckenthaler, “Iron toxicity in diseases of aging: alzheimer's disease, Parkinson's disease and atherosclerosis,” Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 879–895, 2009.
[41]
M. Thomas and J. Jankovic, “Neurodegenerative disease and iron storage in the brain,” Current Opinion in Neurology, vol. 17, no. 4, pp. 437–442, 2004.
[42]
A. Khanna, S. Muthusamy, R. Liang, H. Sarojini, and E. Wang, “Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice,” Aging, vol. 3, no. 3, pp. 223–236, 2011.
[43]
J. M. Timmins, L. Ozcan, T. A. Seimon et al., “Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways,” Journal of Clinical Investigation, vol. 119, no. 10, pp. 2925–2941, 2009.
[44]
M. E. Kalaitzakis, M. B. Graeber, S. M. Gentleman, and R. K. B. Pearce, “The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson's disease: a critical analysis of α-synuclein staging,” Neuropathology and Applied Neurobiology, vol. 34, no. 3, pp. 284–295, 2008.
[45]
Louis, E. D. Babij R, E. Cortés, J. P. Vonsattel, and P. L. Faust, “The inferior olivary nucleus: a postmortem study of essential tremor cases versus controls,” Movement Disorders, vol. 28, no. 6, pp. 779–786, 2013.
