Preclinical Screening of Compounds that Modulate the Pathological Interplay between Alpha-synuclein and Synapsin III for the Treatment of Parkinson’s Disease

Study Rationale: The protein alpha-synuclein forms abnormal aggregates in the brains of people with Parkinson's disease (PD). Although the mechanism by which this aggregation leads to the pathological changes associated with PD is not entirely clear, it is believed to control the release of dopamine at synapses, the points of contact between neurons. This dopamine release requires the assistance of another protein, called synapsin III. We have determined that pathological forms of synapsin III mediate the deposition of alpha-synuclein and the associated death of dopamine-producing neurons. We have therefore developed novel compounds for disrupting the pathological interplay between alpha-synuclein and synapsin III.

Hypothesis: We hypothesize that reestablishing functional interactions between between alpha-synuclein and synapsin III—and reducing their pathological interplay—will inhibit alpha-synuclein aggregation and promote the appropriate release of dopamine, slowing the progression of PD.

Study Design: We will use preclinical models of PD, including organoids grown from cells derived from people with PD, to assess the pharmacological profile of our novel compounds and study whether they can reduce the pathological deposition of alpha-synuclein, halt the loss of neurons and restore dopamine release and motor abilities.

Impact on Diagnosis/Treatment of Parkinson’s disease: The therapeutic readout of this project involves assessing whether the compounds we have developed for modulating alpha-synuclein/Synapsin III interaction can promote motor recovery and counteract pathological protein aggregation and neurodegeneration. The approach could lead to a novel therapeutic for managing PD symptoms and modifying the course of disease progression.

Next Steps for Development: If our investigations show that these novel compounds possess a suitable pharmacological profile as PD therapeutics, we plan to further corroborate their efficacy and safety profile in additional experimental models and pursue a Phase 1 clinical trial.