Drug Discovery for Parkinson's Disease

Despite recent advances in the symptomatic treatment of Parkinson's disease, there are currently no interventions that halt or reverse the progression of this debilitating disease. The market for Parkinson's disease therapeutics is small compared to diseases with much higher incidence (cancer or heart disease, for example) and, as a result, there is little incentive for significant Parkinson's disease drug discovery programs within the pharmaceutical industry. Together, these facts highlight the great need to de-risk novel therapeutic targets and strategies for the treatment of Parkinson's disease. Inhibition of alpha-synuclein oligomerization is one of these novel strategies.

The approach of Dr. McLean's lab facilitates rapid screening of compound libraries for chemicals that target the oligomeric stage of fibrillization, where rescue of the soluble monomeric forms of alpha-synuclein could potentially rescue cell death, slow disease progression, and thus be potential candidate compounds for disease modifying therapeutics. Dr. McLean's lab has performed high-throughput screens for compounds that directly inhibit oligomer formation and oligomer-induced toxicity using a sensitive, cell-based protein complementation assay (PCA) to monitor oligomeric alpha-synuclein.

Although the mechanisms of alpha-synuclein aggregation and its related cytotoxicity remain elusive, molecules with aggregation-prevention properties represent potential disease-modifying therapeutic agents. If successful this work will yield first-in-class chemical probes for lead-optimization and structure-based drug design studies and will serve to validate the therapeutic hypothesis that blocking alpha-synuclein aggregation is an effective therapy for Parkinson's disease and other synucleinopathies.