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

• Published in: Neurochemistry international 2013-04, Vol.62 (5), p.637-652
• Main Authors: Funke, Claudia, Schneider, Susanne A., Berg, Daniela, Kell, Douglas B.
• Format: Article
• Language: English
• Subjects: Biocatalysis; Brain - metabolism; Cell Death; GWAS; Holistic analysis; Humans; Iron; Iron - metabolism; Organelles - metabolism; PARK genes; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson’s disease; Systems Biology
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2012.11.015

► Multiple genes have been found to be associated with Parkinson’s disease. ► Much evidence shows that unliganded iron is also heavily involved. ► The gene products are involved in metabolic and signalling pathways. ► A systems biology approach allows one to account for these effectively. ► We therefore provide a unifying explanation of disease development. 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.