Neuronal autophagy in neuro-protection and implication of deregulated autophagy in neurodegeneration
Autophagy is a highly regulated, cellular "self-eating" pathway involving dynamic membrane rearrangement and degradation through lysosome. The emerging evidence shows that autophagy is an essential mechanism for protein quality control and membrane homeostasis in neurons. The impairment of autophagy in CNS contributes to accumulation of ubiquitinated proteins, axonal dystrophy (axonopathy) and neurodegeneration. The research in my laboratory is focusing on characterization of the roles of autophagy in trafficking and degradation of ubiquitinated proteins, as well as interaction of autophagy with axonal transport process. The goal of our study is to gain insight into the control mechanisms of autophagy and dysfunctional autophagy underlying several major human neurological disorders such as Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis and Alzheimer's disease, and to provide new avenues for both diagnosis and targets of therapeutic treatment of those diseases.
Activated Autophagy In Axonal Dystrophic Swelling
Characterization of physiological protein complexes essential for mammalian autophagic activity
We are developing a new research paradigm that is widely applicable to the study of protein complexes in mammalian physiology. This paradigm will integrate multi-discipline research to systematically study physiological and dynamic composition of protein complexes in mammalian tissues. We will use mammalian autophagy as a model system to dissect sophisticate molecular process based on the understanding of the behavior of autophagic protein complexes. We are particularly interested in addressing neuronal autophagic activity during aging process and neurological disorders such as Parkinson's disease and Alzheimer's disease.
Molecular mechanisms for the pathogenesis of Parkinson's Disease
The Parkinson's disease (PD) is a movement disorder characterized clinically by rigidity, resting tremor and bradykinesia. The pathological features of PD include the deposit of Lewy body comprising mainly fibril alpha-synuclein and nigral degeneration. Recent discovery of mutations of LRRK2 which cause the most common familial PD presents an opportunity to investigate in detail the mechanisms or pathways contributing to pathogenesis of PD. Recent evidence also suggests that LRRK2 may be a central control governing multiple signaling pathways. Our study is focusing on detecting LRRK2-mediated cellular functions or pathways and characterizing the pathogenic mechanisms of familial PD mutation (such as R1441G and G2019S). Our research is expected to expand current understanding of PD pathogenesis at cellular and molecular levels by specifically deciphering LRRK2-binding proteins and dissecting the LRRK2-mediated molecular pathway. It will provide valuable information for PD therapeutic design directed towards enzymatic activity of LRRK2 containing Ras GTPase and MAPKKK kinase domains. We are also interested in translating our knowledge directly from our basic mechanistic study to the identification of the drug targets and the screening of the chemicals against the drug targets.
Distribution of LRRK2 protein in adult mouse CNS
My lab research employs a range of experimental approaches including mouse molecular genetics (such as BAC-mediated transgenic and conditional gene targeting), immunohistochemistry, biochemistry and cell biology. We are collaborating with world-renowned experts in mass spectrometry, bioinformatics protein structure and system biology to facilitate the productivity of research.
- The Michael J. Fox Foundation for Parkinson’s Research
Yue (PI); 1/1/2008-12/31/2010
Using BAC transgenic mice to determine causative role of LRRK2 kinase activity in PD pathogenesis
- RO1 R01NS060123-01A1 NIH/NINDS
Yue (PI); 4/1/2008-3/31/2013
“Neuronal Autophagy: a Cell-Autonomous Protection Mechanism”
The major goal is to investigate autophagy in axon physiology and axonopathy associated with human neurological disorders.
- R21NS061152-01 NIH/NINDS
(Yue, Z); 07/01/2008-06/30/2010
“Exploration of Cognitive Impairments in BAC-Mediated LRRK2 Transgenic Mice”
The major goal is to analyze possible non-motor symptom of PD in LRRK2 transgenic mice
- RO1 NS060809-01 NIH/NINDS
(Yue, Z); 07/01/2008-06/30/2013
“Using BAC-transgenic and Proteomic Approach to Study LRRK2 Biology and Pathology”
The major goal is to understand the cellular function of LRRK2 and the relevance to PD pathogenesis
- The Michael J. Fox Foundation for Parkinson’s Research, Therapeutics Development Initiative (TDI); 02/01/2009- 01/31/2011