Alpha-synuclein Toxicity in LRRK2 Knock-in Models and Rescue by LRRK2 Silencing

Study Rationale:
Gene mutations that alter the function of the LRRK2 protein are known to increase the risk of developing Parkinson’s disease (PD). One of the pathological hallmarks of PD is the presence of protein clumps in brain cells composed mainly of alpha-synuclein. Recent work has shown that PD-like pathology can be induced in models by exposure to pathogenic forms of alpha-synuclein in distinct conformations known as pre-formed fibrils (PFFs). We predict LRRK2 is involved in alpha-synuclein PFF-induced pathology. Previous work from our group has shown that gene silencing of LRRK2 is quite well-tolerated in the brain, suggesting that we might be able to prevent the pathology induced by alpha-synuclein PFFs in LRRK2 PD models by eliminating LRRK2 protein.

Hypothesis:
LRRK2 is involved in alpha-synuclein PFF-induced pathology. Silencing of LRRK2 will reduce the toxic effects of PFFs in these models.

Study Design:
We will test cognitive and motor function in LRRK2 knock-in models before and after exposure to alpha-synuclein PFFs and later assess the presence of pathology. In a subset of these models, we will also using pharmacological treatments to eliminate the LRRK2 protein in an attempt to arrest or reverse the pathological processes induced by alpha-synuclein PFFs.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
LRRK2 silencing may be protective against the development of Parkinson’s disease. Demonstrating that LRRK2 silencing protects the brain from PD-like pathology in models will provide evidence in favor of this strategy for neuroprotection. Similar silencing strategies are being tested in patients with other neurodegenerative diseases, and the data this study produces may help us develop a treatment for those with, and those at increased risk of developing, PD and other synucleinopathies.

Next Steps for Development:
Successful protection from pathology in preclinical models is necessary to translate proof-of-concept strategies to clinical trials. Similar technology is already in human trials for other diseases, and a positive outcome here would provide the first efficacy and safety data that are a (partial) pre-requisite for human tests.