Objective/Rationale:
Using stem cell-derived neurons from individuals with Parkinson’s disease, we have found that dopaminergic neurons carrying the G2019S variant of LRRK2 are abnormally sensitive to immune system molecules that naturally increase in the body with age. Neurons exposed to immune signaling molecules activate genes that control connectivity to other neurons and our hypothesis is that some forms of Parkinson’s disease may be caused by an amplified disconnection of neurons. The objectives of this project are to determine if immune-related disconnectivity is common in other individuals with Parkinson’s disease.
Project Description:
The project has three major aims. The first is to determine if stem cell derived neurons from other individuals with LRRK2 G2019S alterations share the same characteristics of immune sensitivity. In the second aim, we will test whether the predicted immune-related disconnection can be confirmed and quantified using neurons in a Petri dish. It is known that for most types of neurons, disconnection from other neurons is stressful and can even trigger cell death. In our final aim, we will test whether neurons that have become partially disconnected show signs of increased stress and cell death.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If the predicted disease mechanisms are commonly found in individuals with LRRK2 alterations, then the stem cell methods developed in this work can be used as a diagnostic tool to identify vulnerable individuals, even before signs of PD have become pronounced. The assay methods can also be used to screen for novel drugs that may slow or prevent disease in individuals whose neurons vulnerable to this disease mechanism. Drugs are being developed to normalize LRRK2 function and there are several clinically-approved drugs that have not been tested in PD but may be relevant to these mechanisms and could represent early opportunities for intervention.
Anticipated Outcome:
Sensitivity to immune signaling molecules is the one of the most pronounced features observed in neurons from Parkinson’s patients to date. Other variants of the LRRK2 gene may produce similar features and our expectation is that most, if not all, PD-related LRRK2 variants alter neuronal response to immune signals and cause disease by inducing an immune-related disconnection and cell death.