In our pursuit to decipher the roles played by PD gene products, we employ a translational approach, which involves developing pre-clinical cellular and animal models of PD. These models encompass knockin, knockout, transgenic, and viral-mediated gene transfer rodent models. We utilize a wide array of cutting-edge techniques from the fields of molecular and cell biology, biochemistry, animal behavior, histology, and microscopy. Our primary goal is to ascertain how mutations in PD-associated genes contribute to neuronal toxicity and eventual neuronal cell death in living organisms.

Recently, our research has been concentrated on uncovering the significance of the gene responsible for encoding leucine-rich repeat kinase 2 (LRRK2, also known as PARK8). Mutations in LRRK2 are the most prevalent genetic anomalies observed in PD patients. LRRK2 is a dual enzyme protein, exhibiting both GTPase and kinase activities, rendering it an appealing target for potential PD therapies (Figure 1). The most common LRRK2 mutation, G2019S, resides in its kinase domain and results in an abnormal elevation in its kinase activity. Through the development of a rat model that overexpresses LRRK2 using recombinant human adenovirus serotype 5 (Ad5) as a gene transfer vector, we have demonstrated that G2019S LRRK2 triggers dopaminergic neuron death in the rat brain in a manner dependent on both its GTPase and kinase functions (Figure 2).

Our forthcoming research endeavors will focus on two primary objectives:

1. Clarifying the roles of LRRK2 substrates in mediating neurodegeneration in living organisms.
2. Assessing therapeutic approaches designed to reduce LRRK2 kinase activity as a potential treatment strategy for PD.