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Neurochem Int. 2013 Apr;62(5):637-52. doi: 10.1016/j.neuint.2012.11.015. Epub 2012 Dec 7.

Genetics and iron in the systems biology of Parkinson's disease and some related disorders.

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1
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Strasse 27, 72076 Tübingen, Germany.

Abstract

The systems biology approach to complex diseases recognises that a potentially large number of biochemical network elements may be involved in disease progression, especially where positive feedback loops can be identified. Most of these network elements will be encoded by genes, for which different alleles may affect the network(s) differentially. A primary requirement is therefore to determine the relevant gene-network relationships. A corollary of this is that identification of the network should thereby allow one to 'explain' or account for any genetic associations. We apply this approach to Parkinson's disease, a disease characterised by apoptotic death of neurons of the substantia nigra, and coupled significantly to a derangement of iron metabolism. We thereby account for the involvement of various genes and biochemical pathways associated with Parkinsonism, including seemingly unconnected ones involving iron, α-synuclein, parkin, mitochondrial respiration and biology, ceramide production, lysosome biology, Lewy body formation, and so on. Although such an analysis necessarily recognises that there is no unitary 'cause' of Parkinson's, it also recognises that each of the elements contributing can or does effectively converge on a particular mode of apoptotic cell death in dopaminergic neurons, often involving iron-mediated hydroxyl radical formation. Overall, the systems biology approach allows us to propose at least one coherent synthesis of the rather disparate literature surrounding the aetiology of Parkinson's disease, and thereby to suggest some (synergistic) targets for ameliorating the disease and its progression.

PMID:
23220386
DOI:
10.1016/j.neuint.2012.11.015
[Indexed for MEDLINE]
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