Objective/Rationale:
Mutations in the LRRK2 gene are the most common genetic cause of classic or typical Parkinson’s disease (PD). One mutation, G2019S, is especially frequent in Jewish (about 14%) and North African Berber (30-40%) patients with PD. Not all LRRK2 mutation carriers, however, develop PD. Studies of Jewish LRRK2 carriers estimate that only 25-35% of gene carriers ever develop symptoms. Also, the clinical features or expression of this mutation is broad; PD can begin early or late in life and its course is variable. The factors, genetic or environmental, that influence whether or how this mutation is expressed are unknown. Understanding these factors or modifiers should help us understand how LRRK2 causes PD and also help in developing new treatments.
Project Description:
In order to gain insight into how LRRK2 causes PD, including possible gene modifiers, this grant focuses on studying PD in Jews, especially individuals and families with the LRRK2 G2019S mutation. Three centers with established Jewish PD populations, Beth Israel Medical Center (New York City), Columbia University (New York City) and Tel Aviv University will be working together to study approximately 2000 Jewish PD patients; in this group about 280 (14%) will have the G2019S LRRK2 mutation. A group of 150 LRRK2 positive and LRRK2 negative patients and their family members will be studied in detail in order to more fully characterize the clinical features of LRRK2, and also to determine early preclinical PD markers (for example, changes in smell, imaging, gait, handwriting and blood markers). Identifying very early PD markers is important for future studies aimed at early treatments to prevent PD symptoms. In order to determine genetic or environmental factors that may influence whether or how the LRRK2 gene is expressed, DNA variations and expression, and environmental exposures will be examined in LRRK2 positive PD families (including family members with the mutation who do not have symptoms of PD), Jewish PD patients without LRRK2 and healthy controls. Genetic and environmental factors that are associated with developing PD will be sought, including factors that interact with LRRK2. Finally, this grant will describe the attitudes of Jewish PD patients and their families towards genetic testing.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This study is relevant to both treatment and diagnosis of PD. In order to identify better treatments we need to understand how LRRK2 causes PD. For this we need to know the modifiers of LRRK2 expression (i.e. why do only 30% of gene carriers develop PD) and we need to understand the pathways involved in its molecular expression. These are goals of this study. Our study also will enhance the way we perform treatment trials and our approaches to diagnosis. That is, in order to be able to examine whether a drug or treatment can prevent or slow PD, we need to be able to identify individuals at high risk for PD and to track disease progression; this study will help determine the tests or markers that identify individuals at highest risk and how these tests change over time and relate to clinical signs of PD.
Anticipated Outcome:
The main outcome is that we will learn about how and why the LRRK2 G2019S mutation expresses itself. This study will determine the symptoms and signs of LRRK2, including the earliest signs of PD. This study will also seek to identify factors that cause LRRK2 gene carriers to develop or not develop PD, including the examination of how gene expression overall is altered in LRRK2. There are several other outcomes including: the possible identification of other gene variants that increase risk for PD in Jews; the determination of tests or biomarkers that can be used to identify people who are at high risk for developing PD; and learning about patients and families attitudes towards genetic testing.