Mutations in the LRRK2 gene may contribute to the development of familial and sporadic Parkinson’s disease (PD). Examination of the physiological role of the LRRK2 protein under healthy conditions is crucial to understanding the function of mutated forms of the gene. By investigating different signaling pathways in LRRK2-deficient pre-clinical models, we will explore how LRRK2 may be involved in the regulation of insulin signaling. The aim of the study is to gain further insight into the role of LRRK2 in insulin signaling and how this pathway could potentially represent a new therapeutic target for PD.
Based on our preliminary data, we found that LRRK2 may be a cellular control element responsible for the deactivation of insulin signaling. This evidence suggests that LRRK2 may prevent continuous intracellular “hyperactivity” of this pathway, which ultimately leads to cell death.
The main goal of the study is to investigate the physiological role of wildtype (normal) LRRK2 in insulin signaling. Using fibroblasts (connective tissue cells) and monocytes (white blood cells) from LRRK2-deficient pre-clinical models, we will study the activation and inactivation of insulin signaling in the absence of LRRK2 by investigating the activity of different signaling proteins. Additionally, we will also how the insulin receptor (the insulin signal acceptor) is recylcled. Furthermore, using fibroblasts from patients with Parkinson’s disease, we will investigate the effects of the known pathogenic LRRK2 mutation G2019S on insulin signaling.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We believe that our data will have an important impact on the development of novel treatment options for PD. We also hope to gain more insight into LRRK2-associated disease pathways. Since several clinical studies have shown a high risk of PD onset in patients with diabetes, our data may help us better understand the molecular link between both diseases and set the foundation for the development of novel therapeutic targets in PD.
Next Steps for Development:
This study represents the first step in characterizing a novel model for LRRK2-associated disease in order to determine a possible role for LRRK2 in insulin signaling. If this study is successful, the next step would involve investigation of the LRRK2/insulin axis in neurons, such as dopaminergic neurons generated from induced pluripotent stem cells. Furthermore, if a molecular rationale is identified, the effect of a low-sugar/carbohydrate diet on PD progression may be tested in a clinical study.