Objective/Rationale:
Alpha-synuclein is a prime target for Parkinson’s disease (PD). Excessive phosphorylation of alpha-synuclein can contribute to pathology, thus mechanisms to decrease its phosphorylation may have therapeutic benefit. Protein phosphatase 2A (PP2A) dephosphorylates alpha-synuclein. We have identified a mechanism that can be safely inhibited with small molecules to increase PP2A activity, reducing biochemical and behavioral abnormalities in pre-clinical models. Our studies will identify novel molecules acting through this mechanism as disease modifying therapeutics for PD.
Project Description:
Phosphorylation of alpha-synuclein has been found to affect its aggregation, therefore means to reduce its hyperphosphorylation are predicted to be of therapeutic utility. We have focused on enhancing activity of alpha-synuclein dephosphorylation by protein phosphatsase 2A (PP2A). A lead compound PP2A activator has been identified that is orally bioavailable and efficacious in pharmacological and genetic models of PD. The compound works through modulating the methylation status of PP2A, a critical post-translational modification that regulates PP2A assembly and activity. This mechanism affects a subset of PP2A that acts on specific substrates, including alpha-synuclein, and therefore can be safely modulated for therapeutic benefit. The initial compound will be further modified to improve its pharmaceutical properties and develop a new chemical entity for clinical development.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Modulation of PP2A activity has the promise to develop a first in class disease modifying therapeutic that acts at the core of the disease process. There are currently no PD therapies available that directly affect alpha-synuclein or approaches that act beyond the symptoms of disease. Such a therapeutic would prevent, or halt the progression of disease, acting beyond affecting only the symptoms of PD and provide significant benefit to patients.
Anticipated Outcome:
Completion of this project will provide a lead compound, acting through an entirely novel mechanism, to enter clinical development. Improving pharmaceutical properties will increase bioavailability and exposure of compound whilst maintaining efficacy of our current lead. This optimized compound will allow for efficient clinical development for PD.