Explore the Pathogenic Mechanisms of LRRK2-Related Parkinson’s Disease---The Metabolomic Profiling in LRRK2 Transgenic Mouse Models, (G2385r) LRRK2 Patients and Asymptomatic Carriers

Background Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder in the elderly population. To discover reliable biomarkers that can be used for early diagnosis and tracking disease progression are an critical but unmet needs for PD. The techniques of“-omics”, which can be applied to various biological media, may be potential for the development of biomarkers for PD. Obtaining plasma, saliva or urine is non-invasive, faster and easier, and may be more acceptable to patients. Metabolomics is the quantitative measurement of a large number of low molecular weight molecules. Metabolomics approaches provide an extensive overview of the biochemical events, metabolic pathways and interaction in cells, tissues, and even an entire living system. Recently, metabolomic profiling has proved to be useful to study neuropsychiatric diseases, including Huntington’s disease and schizophrenia. The metabolomic profiles of plasma were quite different between PD patients and healthy aging people. The underlying pathology in PD is the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). However, the pathogenic mechanism of DA neuronal death in PD is still unclear. PD is a heterogeneous, multifactorial syndrome. Mutation in the leucine-rich repeat kinase-2 (LRRK2) gene is the most frequent identified genetic cause in PD. (G2019S) is the most frequent identified pathogenic mutation of LRRK2 in Caucasian population, whereas polymorphic (G2385R) LRRK2 mutation is a genetic risk factor for sporadic PD patients of Chinese ethnicity. The pathogenesis of the (G2385R) LRRK2-related PD is still unclear. Recently, a metabolomics study showed that (G2019) LRRK2 patients had unique metabolomics profiles that distinguish them from patients with idiopathic PD. Asymptomatic (G2019S) LRRK2 carriers also had different metabolomics profiles compared with gene negative family members. Therefore, metabolomic profiles could be useful in predicting which LRRK2 carriers will eventually develop PD. To date, the metabolomics profiles of (G2385R) LRRK2 PD patients and asymptomatic carriers have never been studied. We had generated the (G2385R) LRRK2 mouse model. The mice will not present PD phenotype and have no DA neuronal death till age of 20 months. However, the mice will develop PD after MPTP treatment, which indicate a higher susceptibility to oxidative stress. The G2385R mutation plays as a risk factor of PD in the mouse model. The pathways that involve the susceptibility are unknown. Metabolomics study should be helpful to explore the pathogenic mechanism of LRRK2-related PD. Objectives The objective of this translation study is to analyze the difference of metabolomic profiling in (G2385R) LRRK2 transgenic mouse models, idiopathic PD patients, PD patients carrying (G2385R) LRRK2 mutation and the asymptomatic carriers. The potential biomarkers for monitoring disease progression and the pathogenic mechanisms of LRRR2-related PD will be further explored. Materials and Methods First year: animal study 10-month-old (G2385R) LRRK2 transgenic mice and wild-type FVB/N mice will be treated with 25mg/Kg MPTP or normal saline respectively, with introperitoneal injection twice per week for 10 weeks. After complete the treatment, the mice will be sacrificed. Frozen samples of brain tissue will be further prepared for metabolomic studies according the standardized procedures. Second year: human study Total 160 subjects will be enrolled, including 40 healthy subjects and 120 idiopathic PD patients with mild, moderate or advanced stage of disease (40 subjects in each group). Third year: human study The second step is to compare the plasma metabolomics in 40 healthy subjects, 40 (G2385R) LRRK2 PD patients, 40 idiopathic PD patients and 40 asymptomatic carriers. Venous blood samples (10 ml) will be obtained. The samples will be transfer to the Metabolomics Core Laboratory, CGU. The metabolomic analysis will be performed according to the standard procedures of LC-MS (liquid chromatography-mass spectrometry)/ UPLC-TOFMS (ultra-performance liquid chromatography (UPLC), coupled with time-of-flight mass spectrometry).

Project ID:PC10308-1877
External Project ID:MOST103-2314-B182-025-MY3