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Gene expression profiling of sporadic Parkinson's disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70.
Ann N Y Acad Sci. 2005 Aug; 1053:356-75.AN

Abstract

Sporadic Parkinson's disease (PD) constitutes 99% of the disorder, while the remaining 1% of the cases is of familial (genetic) origin. The mutations reported to be associated with familial PD indicate impairment in protein processing and misfolding, as is handled by the ubiquitin-proteasome system (UPS), and in mitochondrial function. For these reasons, we have recently applied, for the first time, Affymetrix oligonucleotide microarray technique in the substantia nigra pars compacta of sporadic parkinsonian patients for studying global gene expression analysis and comparison to the alterations identified in inherited PD. This study identified decreased expression of 68 genes and elevation of 69 genes. Classification into functional groups revealed that the downregulated genes are related to signal transduction, protein degradation (e.g., ubiquitin-proteasome subunits), dopaminergic transmission/metabolism, iron transport, protein modification/phosphorylation, and energy pathways/glycolysis functional classes. A major finding is the decreased expressions of 5 subunits of the UPS, SKP1A, a member of the SCF (E3) ubiquitin ligase complex, and chaperone HSC-70, which can lead to a wide impairment in the function of an entire repertoire of proteins. The upregulated genes are clustered in cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism and transcription, and inflammation/hypoxia (e.g., key iron and oxygen sensor EGLN1) classes. The study shows, for the first time, a convergence in the pathogenic processes that are observed in hereditary (familial) and sporadic PD, where abnormal iron metabolism, oxidative stress, and aggregation of proteins occur. An additional breakthrough in this research is the identification of a number of previously unsuspected crucial gene players that are also involved in the process of neurodegeneration, which can serve as specific biomarkers for PD and novel drug development.

Authors+Show Affiliations

Eve Topf and USA National Parkinson Foundation Centers of Excellence and Department of Pharmacology, Family Research Institute, Technion-Rappaport Family Faculty of Medicine, Haifa, Israel.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

16179542

Citation

Mandel, Silvia, et al. "Gene Expression Profiling of Sporadic Parkinson's Disease Substantia Nigra Pars Compacta Reveals Impairment of Ubiquitin-proteasome Subunits, SKP1A, Aldehyde Dehydrogenase, and Chaperone HSC-70." Annals of the New York Academy of Sciences, vol. 1053, 2005, pp. 356-75.
Mandel S, Grunblatt E, Riederer P, et al. Gene expression profiling of sporadic Parkinson's disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. Ann N Y Acad Sci. 2005;1053:356-75.
Mandel, S., Grunblatt, E., Riederer, P., Amariglio, N., Jacob-Hirsch, J., Rechavi, G., & Youdim, M. B. (2005). Gene expression profiling of sporadic Parkinson's disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. Annals of the New York Academy of Sciences, 1053, 356-75.
Mandel S, et al. Gene Expression Profiling of Sporadic Parkinson's Disease Substantia Nigra Pars Compacta Reveals Impairment of Ubiquitin-proteasome Subunits, SKP1A, Aldehyde Dehydrogenase, and Chaperone HSC-70. Ann N Y Acad Sci. 2005;1053:356-75. PubMed PMID: 16179542.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene expression profiling of sporadic Parkinson's disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. AU - Mandel,Silvia, AU - Grunblatt,Edna, AU - Riederer,Peter, AU - Amariglio,Ninette, AU - Jacob-Hirsch,Jasmine, AU - Rechavi,Gideon, AU - Youdim,Moussa B H, PY - 2005/9/24/pubmed PY - 2006/6/7/medline PY - 2005/9/24/entrez SP - 356 EP - 75 JF - Annals of the New York Academy of Sciences JO - Ann N Y Acad Sci VL - 1053 N2 - Sporadic Parkinson's disease (PD) constitutes 99% of the disorder, while the remaining 1% of the cases is of familial (genetic) origin. The mutations reported to be associated with familial PD indicate impairment in protein processing and misfolding, as is handled by the ubiquitin-proteasome system (UPS), and in mitochondrial function. For these reasons, we have recently applied, for the first time, Affymetrix oligonucleotide microarray technique in the substantia nigra pars compacta of sporadic parkinsonian patients for studying global gene expression analysis and comparison to the alterations identified in inherited PD. This study identified decreased expression of 68 genes and elevation of 69 genes. Classification into functional groups revealed that the downregulated genes are related to signal transduction, protein degradation (e.g., ubiquitin-proteasome subunits), dopaminergic transmission/metabolism, iron transport, protein modification/phosphorylation, and energy pathways/glycolysis functional classes. A major finding is the decreased expressions of 5 subunits of the UPS, SKP1A, a member of the SCF (E3) ubiquitin ligase complex, and chaperone HSC-70, which can lead to a wide impairment in the function of an entire repertoire of proteins. The upregulated genes are clustered in cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism and transcription, and inflammation/hypoxia (e.g., key iron and oxygen sensor EGLN1) classes. The study shows, for the first time, a convergence in the pathogenic processes that are observed in hereditary (familial) and sporadic PD, where abnormal iron metabolism, oxidative stress, and aggregation of proteins occur. An additional breakthrough in this research is the identification of a number of previously unsuspected crucial gene players that are also involved in the process of neurodegeneration, which can serve as specific biomarkers for PD and novel drug development. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/16179542/Gene_expression_profiling_of_sporadic_Parkinson's_disease_substantia_nigra_pars_compacta_reveals_impairment_of_ubiquitin_proteasome_subunits_SKP1A_aldehyde_dehydrogenase_and_chaperone_HSC_70_ L2 - https://doi.org/10.1196/annals.1344.031 DB - PRIME DP - Unbound Medicine ER -