The long-term goal of the Yue Laboratory is to understand cellular and molecular mechanisms of neurodegeneration and develop therapeutic strategies to treat neurological diseases. Dr. Yue’s group focuses on elucidation of cellular process and regulation of autophagy-lysosome pathway in neurons, and understanding the involvement of autophagy in various neurological disorders including Parkinson’s, Alzheimer’s and Huntington’s diseases. The Yue Lab also investigates the biology and pathophysiology of LRRK2 kinase, which is associated with the most common familial form of Parkinson’s disease.
Molecular and Cellular Process of Autophagy
Autophagy is a highly regulated cell "self-eating" pathway. The fundamental process of autophagy involves packing, trafficking, and delivering of macromolecules and organelles through autophagic vacuoles to lysosomes for degradation. Autophagy is a ubiquitous cellular process that is linked to a variety of physiological functions and pathological conditions in mammals. Our goal is to understand the molecular and cellular mechanism of autophagy. We are currently using a research paradigm that integrates several multidisciplinary approaches, including cell imaging, protein biochemistry, structure biology, and genetic animal models, in order to dissect the autophagic process in vitro and in vivo. Our particular interest is to characterize the dynamic composition and specific function of autophagy protein complexes. By using mammalian autophagy as a model system, we aim to provide mechanistic insight into the cellular trafficking network that is important for the understanding of various neuronal functions and pathogenic processes associated with Parkinson's disease and Alzheimer's disease.
Neuronal Autophagy in Axonal and Neuronal Degeneration
Autophagy plays an important role in the maintenance of cellular homeostasis in neurons. The impairment of autophagy in the CNS contributes to accumulation of ubiquitinated proteins, axonal dystrophy (axonopathy), and neurodegeneration. We aim to investigate the detailed mechanism of autophagy in trafficking and degradation of ubiquitinated protein aggregates, as well as the interaction of autophagy with the axonal transport process. This study is intended to gain insight into the molecular mechanisms whereby autophagy participates in the pathogenic processes of 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.
Molecular mechanisms for the pathogenesis of Parkinson’s disease
Parkinson’s disease (PD) is a movement disorder characterized clinically by rigidity, resting tremor and bradykinesia. The pathological features of PD include nigral degeneration and the deposit of Lewy bodies comprising mainly fibril alpha-synuclein. Emerging evidence links LRRK2 to the most common familial PD and also suggests that LRRK2 is a central control protein that governs multiple signaling pathways. Our short-term goal is to dissect LRRK2-mediated cellular pathways and to elucidate the pathogenic mechanisms of the familial PD mutations of LRRK2 (such as R1441G and G2019S). We are currently engaged in several research programs, including genetic mouse models of PD, electrophysiology, neurochemistry, animal behavior, neuropathology, enzyme chemistry, protein structure/functions, and drug discovery. Our long-term goal is to translate our knowledge from our basic mechanistic studies to the identification of the drug targets and to the development of potential drugs for the treatment of PD.