Genetic mutations that alter the function of the LRRK2 protein increase the risk of developing a form of Parkinson's disease (PD). Age and other environmental factors combine with genetic risk factors to result in the disease. One of the pathological hallmarks of PD is the presence of protein clumps that appear in brain cells, composed of alpha-synuclein and LRRK2. Recent work has shown that Parkinson's disease-like pathology can be induced in cultured cells and pre-clinical models by exposure to forms of the alpha-synuclein protein, in distinct conformations known as pre-formed fibrils. We have genetically engineered models to have the same human-disease causing mutations in LRRK2 genes and have identified several changes in brain function that are similar to those found in human PD. We predict LRRK2 is involved in alpha-synuclein pre-formed fibril-induced pathology and that mutations in these models will make them more vulnerable to cognitive deficits and pathology produced by alpha-synuclein pre-formed fibrils. 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 in alpha-synuclein pre-formed fibrils in LRRK2 models by eliminating the LRRK2 protein.
LRRK2 is involved in alpha-synuclein pre-formed fibril-induced pathology. LRRK2 G2019S models are more vulnerable to the cognitive deficits and pathology produced by in alpha-synuclein pre-formed fibrils. Silencing of LRRK2 will reduce the toxic effects of in alpha-synuclein pre-formed fibrils.
We will test cognitive and motor function in LRRK2 models before and after exposure to in alpha-synuclein pre-formed fibrils and later assess the presence of pathology. We will also use pharmacological treatments to eliminate the LRRK2 protein to stop or reverse the pathological processes induced by in alpha-synuclein pre-formed fibrils.
Impact on Diagnosis/Treatment of Parkinson's Disease:
Recent advances show that LRRK2 parkinsonism is unlikely a result of reduced LRRK2 protein function and more likely a result of increased LRRK2 activity. Evidence also shows that eliminating LRRK2 is not overtly damaging to brain physiology. Thus, LRRK2 silencing may be protective against the development of PD. Demonstrating that LRRK2 silencing protects the brain from PD-like pathology will provide evidence in favor of this strategy for neuroprotection. Similar silencing strategies are being tested in individuals 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 pre-clinical 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 trials.