[en] The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be up-regulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly(ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.
Research center :
Imperial College London
Disciplines :
Neurology
Author, co-author :
Moran, L. B.; Imperial College London > Department of Neuropathology
Croisier, E.; Imperial College London > Department of Neuropathology
Duke, D. C.; Imperial College London > Department of Neuropathology
Kalaitzakis, M. E.; Imperial College London > Department of Neuropathology
Roncaroli, F.; Imperial College London > Department of Neuropathology
Deprez, Manuel ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Dexter, D. T.; Imperial College London > Department of Cellular and Molecular Biology
Pearce, R. K. B.; Imperial College London > Department of Neuropathology
Graeber, M. B.; Imperial College London > Department of Neuropathology
Language :
English
Title :
Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra.
Publication date :
2007
Journal title :
Acta Neuropathologica
ISSN :
0001-6322
eISSN :
1432-0533
Publisher :
Springer Verlag, New York, United States - New York
Volume :
113
Issue :
3
Pages :
253-63
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Parkinson’s Disease Society of the United Kingdom, registered charity 948776.
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