Understanding the molecular basis of Parkinson's disease, identification of biomarkers and routes to therapy.
These are really exciting times in the field of Parkinson's disease research. Although the etiology of sporadic disease still remains a mystery, many of the proteins associated with hereditary disease (5-10% of all disease) have now been identified. Only time will tell whether proteins associated with hereditary disease are involved in the development of sporadic disease. The most valuable proteomic studies performed to date are, and continue to be, those aimed at identifying endogenous binding partners, substrates, post-translational modifications and cellular pathways affected by these proteins. Similar to global proteomic approaches, even these approaches have surprisingly often been characterized by the production of very long lists of proteins. Consequently, the parallel development of more refined protein-protein interactions maps has aided the chance of identifying those protein complexes and/or cellular pathways, which, when disrupted, lead to the development of disease. The knowledge gained from these studies is essential, as targeting the activities of these proteins, or the pathways they operate in, currently offers the best opportunity to develop new therapeutic strategies to treat the disease. They may include agents to modulators of kinase activities (e.g., PINK1 and LRRK2), modulators of the activity of the ubiquitin-protein ligase, Parkin, proteostasis agents to block alpha-synuclein filament assembly and toxicity, or promote the refolding of mutant proteins, modulators of alpha-synuclein transfer between cells, reagents to regulate cargo dynamics along axonal microtubule networks, stimulators of autophagy and/or modulators of cellular stress pathways. The second major challenge will be to identify biomarkers to enable population screening to identify those with asymptomatic early-stage disease. Whether the analysis of blood or urine samples will yield such a marker, remains to be determined. Success or failure will be highly dependent on adopting strict standard operating procedures for the collection, processing and storage of samples, combined with the need for the identification of the most robust methods of prefractionation of samples to remove the most abundant proteins prior to proteomic screening.
Robinson
Philip A
PA
Section of Ophthalmology and Neuroscience, Wellcome Trust Brenner Building, Leeds Institute for Molecular Medicine, St James's University Hospital, Leeds, UK. p.a.robinson@leeds.ac.uk
D015415:Biomarkers / Q000097:blood / Q000652:urine; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends; D006801:Humans; D010300:Parkinson Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D040901:Proteomics / Q000379:methods
D015415:Biomarkers