Understanding the molecular basis of Parkinson’s disease, identification of biomarkers and routes to therapy

Abstract

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 α-synuclein filament assembly and toxicity, or promote the refolding of mutant proteins, modulators of α-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.

Keywords::

• α-synuclein
• DJ-1• HtrA2
• LRRK2
• Parkin
• Parkinson’s disease
• PINK1

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.