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Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra

Moran, L. B., Croisier, E., Duke, Dawn, Kalaitzakis, M. E., Roncaroli, F., Deprez, M., Dexter, D. T. and Pearce, R. K. B (2007) Analysis of alpha-synuclein, dopamine and parkin pathways in neuropathologically confirmed parkinsonian nigra Acta Neuropathologica, 113 (3). pp. 253-263.

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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.

Item Type: Article
Divisions : Researcher Development Programme
Authors :
Moran, L. B.
Croisier, E.
Kalaitzakis, M. E.
Roncaroli, F.
Deprez, M.
Dexter, D. T.
Pearce, R. K. B
Date : 4 January 2007
OA Location : 10.1007/s00401-006-0181-6
Copyright Disclaimer : © Springer-Verlag 2007
Uncontrolled Keywords : Familial Parkinson’s disease genes;Gene regulatory network; Microarrays; Pathway analysis; Systems biology
Depositing User : Jane Hindle
Date Deposited : 22 Jun 2017 10:13
Last Modified : 16 Jan 2019 18:53

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