Study Rationale: The symptoms of Parkinson’s disease (PD) arise when more than 70% of the dopamine-producing neurons in the brain region regulating movement are lost. This disruption increases the stress on the remaining neurons, which have to boost their activity to compensate for the loss and maintain brain function. We hypothesize that this chronic activity overload depletes cells of the energy required for other important processes, including removal of damaged components (a process called autophagy) and molecular repair. This vicious cycle facilitates further neurodegeneration and accelerates disease progression.
Hypothesis: We hypothesize that chemicals that modulate the activity of ion channels—proteins critical for neuronal activity—can protect against excessive energy depletion in hyperactive human neurons. We further hypothesize that this treatment will enhance autophagy and cellular stress responses—and ultimately slow neurodegeneration in PD.
Study Design: This study will reveal, for the first time, the precise mechanisms underlying the vulnerability of patient-derived neurons to electrical activity overload. We will evaluate the potential of established and novel ion-channel modulators (ICM), derived from naturally occurring spider venoms, to prevent the chronic metabolic exhaustion and death of dopamine-producing neurons. We predict that periodic ICM treatment can halt the vicious cycle perpetuating neurodegeneration in PD. This innovative project will open the way for a new therapeutic pipeline to slow PD progression.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, the study could provide a breakthrough in the treatment of PD. Ion channels are a common target for drug development: Almost 20% of small-molecule therapeutics target ion channels, including many used to treat neurological disease. Venom-based molecules are specific, potent, and fast-acting, making them ideal candidates for therapeutics.
Next Steps for Development: If our hypothesis of ‘electro-pharmaceutic rescue of energy levels in brain cells’ is validated, our findings will pave the way for future clinical trials. Such electro-pharmaceutics for PD would, in turn, have major public health benefits.