Investigating Molecular Pathogenic Mechanisms of Park8 Using Knockin Mouse Model.

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Parkinson’s disease (PD) affects ~ 1 % of the population above the age of 60 and is the most common neurodegenerative motor disorder. The majority (~90 %) of PD cases is sporadic, and Mendelian familial forms of Parkinson’s disease accountfor ~10 % of PD patients. Up to now, the exact molecular mechanisms underlying the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc) and molecular pathogenesis of PD is not completely understood. Identification of genes linked to familiar forms of PD led to a better understanding of novel proteins and molecular pathways that may cause the neurodegeneration of SNpc dopaminergic cells and resulting parkinsonism. Patients with familial type 8 of Parkinson’s disease (PARK8) exhibit late-onset parkinsonism symptoms and autosomal dominant inheritance. Molecular genetic studies identified missense mutations of leucine-rich repeat kinase 2 (LRRK2) as the cause of PARK8. LRRK2 mutation is the most common genetic cause of both familial and sporadic PD cases. Mutations of PTEN-induced kinase 1 (PINK1) gene cause recessive familial type 6 of Parkinson’s disease(PARK6). PINK1 is the second most frequent causative gene in early-onset PD, and PINK1 mutations are also found in sporadic PD patients. Clinical features of PARK8 or PARK6 patients are similar to those of sporadic PD patients, suggesting that common molecular pathogenic mechanisms cause PARK8, PARK6 and sporadic PD. Thus, a better understanding of cellular and molecular mechanisms underlying mutant LRRK2- or PINK1-induced parkinsonism is expected to unravel the pathogenic mechanism of PARK8, PARK6 and sporadic PD. In order to investigate molecular pathogenic mechanisms of PD and develop therapeutic strategy and biomarker of PD, our Integrated Research Project consists of the following three sub-projects: (1) Sub-project 1: Investigating molecular pathogenic mechanisms of PARK8 using knockin mouse model. (2) Sub-project 2: Investigating molecular pathogenic mechanisms of PARK6 using knockin mouse model. (3) Sub-project 3: From mouse models to patients: Development of a novel 18F-DTBZ PET imaging as a biomarker to monitor neurodegeneration of PARK6 and PARK8 parkinsonism. Specific aims of our Integrated Research Project include: (1) To investigate molecular pathogenic mechanisms of PARK6, PARK8 and sporadic PD using PARK6 and PARK8 knockin mouse models. (2) To test possible therapeutic effect of small-molecule LRRK2 inhibitors using PARK8 knockin mouse models. (3) To evaluate 18F-DTBZ PET imaging as a biomarker for disease progression of PARK6, PARK8 and idiopathic PD patients. Long-term objectives of our Integrated Research Project are: (A) PARK6 or PARK8 knockin mice are used to establish a standard and stable animal platform for developing new PD drugs. (B) Discovering new drug or therapeutic strategy of PD for further clinical application. Among LRRK2 mutations found in PARK8 and sporadic PD patients, G2019S and Y1699C are two of the most prevalent mutations. In this sub-project 1 of our Integrated Research Project, animal model of mutant (G2019S) or (Y1699C) LRRK2-induced PD is prepared by generating humanized knockin mice expressing PARK8 mutant (G2019S) or (Y1699C) LRRK2. Then, we will investigate molecular pathogenic mechanisms of (Y1699C) or (G2019S) LRRK2-induced parkinsonism by performing the following experiments using LRRK2Y1699C/+or LRRK2G2019S/+ knockin mice, which display PD neuropathological phenotypes and motor deficits: (1) We will study molecular mechanisms underlying mutant (G2019S) or (Y1699C) LRRK2-induced degeneration of SNpc dopaminergic neurons in LRRK2Y1699C/+or LRRK2G2019S/+ knockin mice. (2) We will test the possibility that mutant (Y1699C) or (G2019S) LRRK2 causes the dysfunction of SNpc dopaminergic or striatal medium spiny neurons of LRRK2Y1699C/+or LRRK2G2019S/+ knockin mice, leading to an impaired motor function of nigrostriatal dopaminergic pathway and parkinsonism. (3) Quantitative phosphoproteomic analysis is performed to identify putative substrates of mutant (Y1699C) or (G2019S) LRRK2 in the brain of LRRK2Y1699C/+or LRRK2G2019S/+ knockin mice. (4)We will test possible therapeutic effect of small-molecule LRRK2 kinase inhibitors on PD neurological phenotypes of LRRK2Y1699C/+ or LRRK2G2019S/+ knockin mice.

Project IDs

Project ID:PC10009-0045
External Project ID:NSC100-2321-B182-008
StatusFinished
Effective start/end date01/08/1131/07/12

Keywords

  • Parkinson’s disease
  • Familial type 8 of Parkinson’s disease (PARK8)
  • Leucine-rich repeat kinase 2
  • Substantia nigra dopaminergic neurons
  • PARK8 knockin mouse

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