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

In both genetic and idiopathic forms of Parkinson's disease (PD), considerable evidence supports the involvement of α‐synuclein, electron transport chain complex I, protein aggregation, and the ubiquitin‐proteasome system. To investigate alterations in the transcription of genes that comprise these pathways, we performed gene expression profiling and functional gene group analysis of three brain regions (the substantia nigra, putamen, and area 9) in postmortem tissue from matched groups of PD or control subjects (n = 15/group). Verification of selected changes was performed using RT‐PCR, and visualization of selected changes in expression was accomplished using in situ hybridization (ISH). Our results provide strong support for the impairment of multiple electron transport chain complexes and the ubiquitin‐proteasomal system in PD, along with a robust induction of heat shock proteins and some anti‐apoptotic gene groups. Several novel gene and gene group findings were also obtained that offer new insight into the pathogenesis and potential treatment of PD. © 2005 Wiley‐Liss, Inc.

[1]  Kuo-Hsuan Chang,et al.  Analysis of heat-shock protein 70 gene polymorphisms and the risk of Parkinson’s disease , 2004, Human Genetics.

[2]  P. Lansbury,et al.  Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. , 2003, Annual review of neuroscience.

[3]  Ken-ichi Isobe,et al.  An inhibitor of mitochondrial complex I, rotenone, inactivates proteasome by oxidative modification and induces aggregation of oxidized proteins in SH‐SY5Y cells , 2003, Journal of neuroscience research.

[4]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[5]  M. Ebadi,et al.  Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons. , 2003, Antioxidants & redox signaling.

[6]  K. O’Malley,et al.  Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons* , 2003, Journal of Biological Chemistry.

[7]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[8]  Lloyd A Greene,et al.  Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease , 2002, The Journal of Neuroscience.

[9]  S. Totterdell,et al.  Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson’s disease , 2002, Brain Research.

[10]  Paul M. McCray,et al.  Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Pierri,et al.  Gene Expression Profiling Reveals Alterations of Specific Metabolic Pathways in Schizophrenia , 2002, The Journal of Neuroscience.

[12]  John Q. Trojanowski,et al.  Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease , 2001, Science.

[13]  Matthew J. Farrer,et al.  α-synuclein gene haplotypes are associated with Parkinson’s disease , 2001 .

[14]  G. Scheper,et al.  The Mitogen-Activated Protein Kinase Signal-Integrating Kinase Mnk2 Is a Eukaryotic Initiation Factor 4E Kinase with High Levels of Basal Activity in Mammalian Cells , 2001, Molecular and Cellular Biology.

[15]  S. Jang,et al.  Polypyrimidine tract-binding protein inhibits translation of bip mRNA. , 2000, Journal of molecular biology.

[16]  Y. Imai,et al.  Parkin Suppresses Unfolded Protein Stress-induced Cell Death through Its E3 Ubiquitin-protein Ligase Activity* , 2000, The Journal of Biological Chemistry.

[17]  Guido Kroemer,et al.  Hsp27 negatively regulates cell death by interacting with cytochrome c , 2000, Nature Cell Biology.

[18]  Luis Carrasco,et al.  A Stable HeLa Cell Line That Inducibly Expresses Poliovirus 2Apro: Effects on Cellular and Viral Gene Expression , 2000, Journal of Virology.

[19]  M. MacFarlane,et al.  Initiation of Apaf-1 translation by internal ribosome entry , 2000, Oncogene.

[20]  M. Clemens,et al.  Changes in integrity and association of eukaryotic protein synthesis initiation factors during apoptosis. , 2000, European journal of biochemistry.

[21]  T. Moos,et al.  The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease , 1999, Neuroscience.

[22]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[23]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[24]  M. Polymeropoulos,et al.  Mapping of a Gene for Parkinson's Disease to Chromosome 4q21-q23 , 1996, Science.

[25]  J. Nathans,et al.  Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[26]  L. Forno,et al.  Neuropathology of Parkinson's Disease , 1996, Journal of neuropathology and experimental neurology.

[27]  Y. Itoyama,et al.  Immunohistochemical localization of the low molecular weight stress protein HSP27 following focal cerebral ischemia in the rat , 1995, Brain Research.

[28]  M. Gaestel,et al.  Small heat shock proteins are molecular chaperones. , 1993, The Journal of biological chemistry.

[29]  C. Marsden,et al.  Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. , 1992, Brain : a journal of neurology.

[30]  A. H. V. Schapira,et al.  MITOCHONDRIAL COMPLEX I DEFICIENCY IN PARKINSON'S DISEASE , 1989, The Lancet.

[31]  Diana Brahams,et al.  Medicine and the Law , 1983, The Lancet.

[32]  F. Middleton,et al.  Application of genomic technologies: DNA microarrays and metabolic profiling of obesity in the hypothalamus and in subcutaneous fat. , 2004, Nutrition.

[33]  C. Olanow,et al.  Proteolytic stress: A unifying concept for the etiopathogenesis of Parkinson's disease , 2003, Annals of neurology.

[34]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[35]  M. Kondoh,et al.  Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. , 2002, The Tohoku journal of experimental medicine.

[36]  A. Poros,et al.  Gaucher disease type I complicated with Parkinson's syndrome. , 2002, Haematologia.

[37]  J. Trojanowski,et al.  Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. , 2002, Science.

[38]  S. Gilman,et al.  Diagnostic criteria for Parkinson disease. , 1999, Archives of neurology.

[39]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.