Study Rationale: The degeneration of neuronal axons is an early pathological feature of Parkinson’s disease (PD) and an attractive target for therapeutic intervention. We have demonstrated that a programmed cell death pathway called necroptosis is involved in this axonal degeneration, and that key components of the necroptotic cascade, including an enzyme called RIPK3, participate in this degeneration in two mouse models of PD. We further demonstrate that pharmacological inhibition of RIPK3 reduces the activation of age-associated necroptosis in the brain and prevents the degeneration of axons and the loss of dopamine-producing neurons in a mouse model of PD based on alpha-synuclein overexpression.
Hypothesis: We hypothesize that RIPK3 inhibition in PD will reduce activation of necroptosis, axonal degeneration and neuroinflammation, thereby decreasing neuropathology and behavioral impairment.
Study Design: In this project, we will target RIPK3 in a mouse model of PD using a combination of pharmacological and genetic methods. This approach will allow us to compare how inhibiting RIPK3 in neurons versus immune cells contributes to protection against neuropathology and behavioral impairment.
Impact on Diagnosis/Treatment of Parkinson’s disease: With the pharmacological and genetic interventions, we will define the contribution made by neuronal versus immune system inhibition of RIPK3 in terms of neuroprotection effect. With the pharmacological studies, we expect to advance a compound close to a Therapeutic Program.
Next Steps for Development: Success of this project will pave the way toward developing new drug designs based on the structure and properties of the most effective RIPK3 inhibitor candidate and by the capacity of this compound to treat PD symptoms and prevent PD progression.