Inhibiting Faulty DNA Repair as a Strategy for Preventing Neuronal Loss in Parkinson’s Disease

Study Rationale: Cells have mechanisms for repairing damaged DNA. Unfortunately, these repair mechanisms can themselves become inefficient and error-prone as we age — leading to the accumulation of toxic intermediates that can injure cells and promote neurodegeneration, a pathology that is associated with Parkinson’s disease (PD). Using a worm model of PD, we discovered that shutting down a mechanism called base-excision repair in mitochondria — cellular structures that are often impaired in PD — prevented the aggregation of alpha-synuclein and led to protection of dopamine-producing neurons. In this project, we will explore the mechanisms driving this neuroprotective response as a strategy for PD intervention.

Hypothesis: Our hypothesis is that inhibition of base-excision repair will be neuroprotective in people with PD, and we aim to study this process to establish new types of interventions.

Study Design: Our project will be divided in three phases. First, we will create dopamine neurons in the lab using stem cells derived from people with PD. We will turn off the base-excision DNA repair pathway in these cells and investigate the mechanisms that drive neuroprotection, with a focus on changes in DNA, gene activity and alpha-synuclein aggregation. To simulate the aging process, we will grow “mini brains” in culture and assess the effects of blocking DNA repair in these organoids. Lastly, we'll evaluate whether chemicals that inhibit DNA repair might prevent aggregate formation and promote neuroprotection as a potential treatment strategy.

Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, the project will confirm that modulation of DNA repair blocks the formation of protein aggregates, a widespread characteristic of PD; our findings therefore represent a potential treatment strategy for PD.

Next Steps for Development: Once our results have been verified in cultured cells and brain organoids, we will confirm them in preclinical animal models with the ultimate goal of launching clinical trials in people with PD.