Objective/Rationale:
Mutations in LRRK2 gene have been identified as an unambiguous cause of rare autosomal dominant forms of PD. A number of useful models have been developed to study the pathobiology of LRRK2, including primary cortical neurons, Drosophila and budding yeast models. However, the pathogenic role and associated biochemical pathways responsible for LRRK2-linked disease remains unclear. This project aims to identify modifiers of LRRK2-induced toxicity based on LRRK2-yeast model and further characterize and validate these modifiers in primary neuronal cultures and the LRRK2 Drosophila model system.
Project Description:
A budding yeast model of LRRK2-induced toxicity has been established recently and revealed a key role of GTPase activity in pathobiology of LRRK2. We have performed a genome-wide genetic screen and identified the modifiers of LRRK2-induced toxicity based on this LRRK2-yeast model. The human homologs of the modifiers of LRRK2-induced toxicity identified from yeast model will be characterized and validated in cell culture and primary neuronal cultures in vitro. To validate the modifiers of LRRK2-induced toxicity in vivo, the human homologues of the yeast modifiers will be tested in preventing or exacerbating dopaminergic neurodegeneration and motor dysfunction in the LRRK2 Drosophila model.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The molecular mechanism and/or pathways by which LRRK2 variants induce neuronal toxicity are poorly understood. The modifiers of LRRK2-induced toxicity identified from a genome-wide genetic screen based on the LRRK2-yeast model will lead to the dissection of the pathways and mechanisms involved in LRRK2-induced toxicity. These modifiers will be evaluated and tested in preventing or exacerbating the dopaminergic neurodegeneration and motor dysfunction in vivo in the LRRK2 Drosophila model, which will point out potential treatment options for LRRK2-associated PD.
Anticipated Outcome:
We have identified the modifiers (suppressors or enhancers) of LRRK2-induced toxicity in yeast model. We anticipate that these modifiers will protect against or exacerbate LRRK2-induced neuronal toxicity in vitro and prevent or exacerbate dopaminergic neurodegeneration and motor dysfunction in the LRRK2 Drosophila model in vivo. We aim to dissect the pathways and mechanisms involved in LRRK2-induced neuronal toxicity and ultimately provide possible therapeutic strategies to treat LRRK2-linked PD.