Identification of genes related to Parkinson's disease using expressed sequence tags.

In a search for novel target genes related to Parkinson's disease (PD), two full-length cDNA libraries were constructed from a human normal substantia nigra (SN) and a PD patient's SN. An analysis of the gene expression profiles between them was done using the expressed sequence tags (ESTs) frequency. Data for the differently expressed genes were verified by quantitative real-time RT-PCR, immunohistochemical analysis and a cell death assay. Among the 76 genes identified with a significant difference (P > 0.9), 21 upregulated genes and 13 downregulated genes were confirmed to be differentially expressed in human PD tissues and/or in an MPTP-treated mice model by quantitative real-time RT-PCR. Among those genes, an immunohistochemical analysis using an MPTP mice model for alpha-tubulin including TUBA3 and TUBA6 showed that the protein levels are downregulated, as well as the RNA levels. In addition, MBP, PBP and GNAS were confirmed to accelerate cell death activity, whereas SPP1 and TUBA3 to retard this process. Using an analysis of ESTs frequency, it was possible to identify a large number of genes related to human PD. These new genes, MBP, PBP, GNAS, SPP1 and TUBA3 in particular, represent potential biomarkers for PD and could serve as useful targets for elucidating the molecular mechanisms associated with PD.

[1]  P. Lackner,et al.  Pathogenic mutations inactivate parkin by distinct mechanisms , 2005, Journal of neurochemistry.

[2]  Richard J Smeyne,et al.  The MPTP model of Parkinson's disease. , 2005, Brain research. Molecular brain research.

[3]  Aaron Ciechanover,et al.  The Ubiquitin Proteasome System in Neurodegenerative Diseases Sometimes the Chicken, Sometimes the Egg , 2003, Neuron.

[4]  W. Dauer,et al.  Parkinson's Disease Mechanisms and Models , 2003, Neuron.

[5]  A. Schapira,et al.  Genetic and environmental factors in the cause of Parkinson's disease , 2003, Annals of neurology.

[6]  H. Chun,et al.  Oxidative stress regulated genes in nigral dopaminergic neuronal cells: correlation with the known pathology in Parkinson's disease. , 2003, Brain research. Molecular brain research.

[7]  Ji Huang,et al.  [Serial analysis of gene expression]. , 2002, Yi chuan = Hereditas.

[8]  M. Soares,et al.  Construction and characterization of a normalized cDNA library. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Y. Wakayama,et al.  Reduced expression of aquaporin 4 in human muscles with amyotrophic lateral sclerosis and other neurogenic atrophies. , 2004, Pathology, research and practice.

[10]  L. Tremblay,et al.  Experimental Models of Parkinson’s Disease , 2002, Annales pharmaceutiques francaises.

[11]  A. Siderowf,et al.  Update on Parkinson Disease , 2003, Annals of Internal Medicine.

[12]  Kazuhiko Matsumoto,et al.  Apoptosis-like cell death of human breast cancer cell line MCF-7 induced by buprenorphine hydrochloride. , 2004, Life sciences.

[13]  L. Greene,et al.  Analysis of gene expression changes in a cellular model of Parkinson disease , 2005, Neurobiology of Disease.

[14]  B. Jortner,et al.  Cytotoxic effects of MPTP on SH-SY5Y human neuroblastoma cells. , 1997, Neurotoxicology.

[15]  N. Zečević,et al.  Interaction between Microglia and Oligodendrocyte Cell Progenitors Involves Golli Proteins , 2005, Annals of the New York Academy of Sciences.

[16]  S. Mandel,et al.  Gene expression analysis in N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mice model of Parkinson's disease using cDNA microarray: effect of R‐apomorphine , 2001, Journal of neurochemistry.

[17]  Sangsoo Kim,et al.  Gene cataloging and expression profiling in human gastric cancer cells by expressed sequence tags. , 2004, Genomics.

[18]  N. Zečević,et al.  Lipopolysaccharide affects Golli expression and promotes proliferation of oligodendrocyte progenitors , 2005, Glia.

[19]  S. Lipton,et al.  Molecular pathways to neurodegeneration , 2004, Nature Medicine.

[20]  F. Dietrich,et al.  Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra , 2005, Movement disorders : official journal of the Movement Disorder Society.

[21]  G. Fu,et al.  Identification of genes expressed in human CD34(+) hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Claverie,et al.  The significance of digital gene expression profiles. , 1997, Genome research.

[23]  L. Penland,et al.  Use of a cDNA microarray to analyse gene expression patterns in human cancer , 1996, Nature Genetics.

[24]  T. Sherer,et al.  Animal models of Parkinson's disease. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[25]  P. Jenner,et al.  Understanding cell death in parkinson's disease , 1998, Annals of neurology.

[26]  Eden Martin,et al.  Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage. , 2003, Human molecular genetics.

[27]  A. Kerlavage,et al.  Complementary DNA sequencing: expressed sequence tags and human genome project , 1991, Science.

[28]  M. Youdim,et al.  Iron and α-synuclein in the substantia nigra of MPTP-treated mice , 2007, Journal of Molecular Neuroscience.

[29]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[30]  Janette K Burgess,et al.  Analysis of gene expression. , 2002, Methods in enzymology.

[31]  B. Aggarwal,et al.  RKIP Sensitizes Prostate and Breast Cancer Cells to Drug-induced Apoptosis* , 2004, Journal of Biological Chemistry.

[32]  Jung-Hwa Oh,et al.  An improved method for constructing a full-length enriched cDNA library using small amounts of total RNA as a starting material , 2003, Experimental & Molecular Medicine.

[33]  S. Mandel,et al.  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 , 2004, Journal of Neural Transmission.

[34]  D. Selkoe,et al.  Cell biology of protein misfolding: The examples of Alzheimer's and Parkinson's diseases , 2004, Nature Cell Biology.

[35]  Nam-Soon Kim,et al.  Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  S. Mandel,et al.  Early and Late Gene Changes in MPTP Mice Model of Parkinson's Disease Employing cDNA Microarray , 2002, Neurochemical Research.

[37]  M. Naoi,et al.  Cell death in Parkinson's disease , 2002, Journal of Neurology.

[38]  Sarah J Tabrizi,et al.  Models of Parkinson's disease , 2003, Movement disorders : official journal of the Movement Disorder Society.

[39]  S. Hirai,et al.  Alpha 1-antichymotrypsin as a possible biochemical marker for Alzheimer-type dementia. , 1990, Annals of neurology.

[40]  L. Steinman,et al.  Transcriptional analysis of targets in multiple sclerosis , 2003, Nature Reviews Immunology.

[41]  S. Hirai,et al.  α1‐Antichymotrypsin as a possible biochemical marker for Alzheimer‐type dementia , 1990 .

[42]  T. Dawson,et al.  Molecular Pathways of Neurodegeneration in Parkinson's Disease , 2003, Science.

[43]  C. Vargas,et al.  Differential Upregulation of Aquaporin-4 mRNA Expression in Reactive Astrocytes after Brain Injury: Potential Role in Brain Edema , 1999, Neurobiology of Disease.

[44]  Kousaku Okubo,et al.  Large scale cDNA sequencing for analysis of quantitative and qualitative aspects of gene expression , 1992, Nature Genetics.

[45]  J. Keller,et al.  Proteasomes and proteasome inhibition in the central nervous system. , 2001, Free radical biology & medicine.

[46]  R. Strausberg,et al.  The Cancer Genome Anatomy Project: EST sequencing and the genetics of cancer progression. , 1999, Neoplasia.

[47]  S. Mandel,et al.  Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (-)-epigallocatechin-3-gallate. , 2004, Journal of molecular neuroscience : MN.

[48]  R. Jensen,et al.  Expression profiling of substantia nigra in Parkinson disease, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism. , 2005, Archives of neurology.

[49]  I. Kondo,et al.  Genetic association between susceptibility to Parkinson's disease and α 1-antichymotrypsin polymorphism , 1997, Brain Research.