3P - Post Doc Seminar - 30 April Join the 3P Seminars for 'Therapies for synucleinopathies' as Diptaman (Neil) Chatterjee, PhD student at Rush University, presents on 'Engineering and Optimizing Delivery of Intracellular Antibody Based therapies for Synucleinopathies' and Liza Bergkvist, Postdoc at the Van Andel Institute discusses 'Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits'. Neil’s presentation includes:Although many therapeutic modalities target extracellular transfer or propagation of alpha-synuclein, protein aggregation initiates intracellularly. We are interested in developing therapeutics that targets intracellular proteinopathy across the brain, particularly in regions susceptible to advanced pathology. We have engineered fully human single-domain antibody fragments that bind to alpha-synuclein to prevent protein aggregation. Using proteasomal targeting sequences, nanobodies can also shuttle excess alpha-synuclein for degradation to limit aggregation. Here, we’ll share data that illustrates target validation in cerebral organoids derived from PD patient iPSCs, and demonstrate the use of engineered AAV9 constructs to facilitate therapeutic distribution throughout the brain. Liza’s presentation features:Epidemiological studies have suggested a link between type-2 diabetes and Parkinson’s disease (PD) risk. Treatment of type-2 diabetes with specific types of insulin sensitizing drugs lower the risk of PD. MSDC-0160, an insulin sensitizer which targets the mitochondrial pyruvate carrier (MPC), was previously shown to ameliorate pathogenesis in acute animal models of PD. Since PD is also characterized by the deposition of a-synuclein (a-Syn), we asked if inhibiting the MPC could directly inhibit a-Syn aggregation in vivo. To this aim, two chronic and progressive animal models; a viral vector-based a-Syn overexpressing model and a PFF a-Syn seeding model, were treated with MSDC-0160 to assess its anti-aggregation properties. We found that a metabolic switch does not alleviate a-Syn toxicity but surprisingly, that it altered the aggregation features of a-Syn in the overexpression model without affecting a-Syn in the seeding model.