Alpha-synuclein and the Parkinson's disease drug pipeline

The process of protein aggregation involves the transformation of soluble peptides into insoluble cross-beta amyloids. In Parkinson's disease (PD), soluble monomeric a-synuclein transforms into the amyloid state known as Lewy pathology. Monomeric (functional) a-synuclein depletes as the fraction of Lewy pathology increases. We examined the allocation of disease-modifying projects in the PD therapeutic pipeline classified based on whether they aimed to reduce directly or indirectly the insoluble or increase the soluble a-synuclein. A project was defined as a drug development program that may include more than one registered clinical trial, ac-cording to the Parkinson's Hope List, a database of therapies under development for PD. Of 67 projects, 46 aimed to reduce a-synuclein, 15 (22.4%) directly and 31 (46.3%) indirectly, amounting to 68.7% of all disease-modifying projects. No projects explicitly aimed to increase soluble a-synuclein levels. Altogether, a-synuclein is the target of more than two-thirds of the disease-modifying pipeline, with treatments aimed at reducing or preventing an increase in its insoluble fraction. As no treatments aim to restore soluble a-synuclein levels within a normal range, we propose rebalancing the therapeutic PD pipeline.