ZhenyuYue_

Molecular, Cellular, network, and Behavioral Mechanisms of Neurological Disorders and Therapeutic Development

The goal of the Yue Laboratory is to elucidate molecular, cellular, network, and behavioral mechanisms of neurological disorders. The Yue Laboratory employs a wide range of experimental and bioinformatic approaches, such as genetic, biochemical, molecular, cellular, transcriptomic (single cell RNAseq), proteomic, network, imaging (live and fixed), animal pathology/behavior, human iPSC neurons/glia and postmortem tissue analysis to dissect autophagy-lysosome, synaptic vesicle trafficking, cell metabolism, neuroinflammation, and protein/lipid kinase signaling in the neuropathogenesis. Our ultimate goal is to translate our knowledge from basic research to the development of molecular diagnostics and therapeutics.

Cell-type specific transcriptomics, molecular pathways and novel therapeutic target identification for Parkinson’s disease (PD)

Genetic linkage and genome wide association studies (GWAS) have begun to gain insight into the molecular mechanism of the PD. However, the vast majority of PD cases have no known genetic cause, and their etiology remains unclear. To dissect molecular mechanisms for dopamine (DA) neuron degeneration, post-GWAS research should investigate in what cell-type PD-linked genes or GWAS variants are actively expressed and how they are affected in vulnerable brain regions of PD. We aim to profile, validate, and characterize molecularly distinct neuron and glia types of PD by using three different biological systems: human postmortem tissues (e.g. SNpc and PFC), genetic mouse models, and induced human neurons (iPSC) 2D/3D midbrain cultures. We will conduct three highly integrated projects: (1) Validating and characterizing distinct DA neuron populations and their PD-associated vulnerability in mouse models through mouse genetics, transcriptomics, whole brain imaging and behavioral analysis; (2) Characterizing molecularly distinct DA neuron populations and their vulnerability in the SN of PD by multiplex RNA and protein spatial profiling, molecular anatomical analysis, and volumetric imaging; (3) Modeling and characterizing human DA neuron subpopulations and their PD-associated vulnerability identified from human SN by using hiPSC-based models.

Circuitry and inflammation mechanism in body-brain interactions during the progression of Parkinson’s disease

An increased incidence of PD in patients with inflammatory bowel disease (IBD), a chronic disease of the gut, has also been reported world-wide. With the finding of a-synuclein-associated Lewy body in peripheral tissues (e.g. gut) of PD patients, there is a growing appreciation for the hypothesis of gut-brain axis and chronic inflammation in the disease onset and progression for PD. The link between intestinal inflammation and PD is also enforced by elevated markers of intestinal inflammation, We aim to determine the subtypes of PD associated with prodromal gut chronic inflammation, dissect the pathogenic mechanism underpinning gut-brain axis, and identify molecular biomarkers and novel therapeutics for subtypes of PD.  We will test the hypothesis that (1) chronic inflammation in the gastrointestinal system contributes to a subset of PD, and this is mediated by pathogenic interaction between LRRK2 and a-synuclein; (2) LRRK2 acts as an interface for the signaling pathways that leads to PD and inflammatory bowel disease (IBD), and investigation of LRRK2 targets (e.g. small GTPase Rab proteins) will help elucidate the molecular mechanisms for the gut-brain axis in the pathogenesis of PD. Our study will provide insight into the PD biomarker development.

The role of microglial autophagy in preventing senescence and offering neuroprotection in Alzheimer’s disease animal models

Autophagy is evolutionarily conserved lysosomal degradation system of the cell. It is a critical pathway that controls cellular homeostasis and can be activated in response to cellular injury or stress. Autophagy is regulated distinctively in different cell types and strongly linked to the pathogenic pathways for neurodegenerative diseases. Our goals are to determine neuroprotective mechanism conferred by microglial autophagy and understand how dysfunctional autophagy in microglia contributes to the pathogenesis of Alzheimer’s disease (AD).  Our central hypothesis is that autophagy activation is required for disease associated microglia (DAM) metabolic fitness, prevention of senescence, and protection of neurons in the AD brains. We will investigate the role of microglial autophagy in controlling inflammation by selective degradation of inflammasomes via protein receptors that are neuroprotective in AD. In addition, we will develop therapeutic strategy to remove senescent microglia for neuroprotection during ageing and disease process.

Autophagy biology in the brain and its dysfunctions in neurons and glial cells in the pathogenesis of Alzheimer’s, Parkinson’s and Huntington’s disease

We propose to elucidate the landscape of autophagy process in the brains. We will investigate cell-type specific autophagy pathways (neuron vs. microglia) under physiological (young and old) and pathological conditions (AD, PD and HD). We will perform a systemic study that integrates multiple genetic mutant lines of mice, human induced neuron lines (hiN), quantitative proteomics, and molecular and cell biology to identify autophagy cargo and receptors in neurons and microglia. We will identify novel autophagy cargo and receptors in mediating autophagy functions in an age and neuron-type specific manner. We will also investigate the distinct mechanisms for the degradation of multiple disease-associated proteins such as tau, aSyn and huntingtin.  Our study will pave the way to identify novel therapeutic targets of autophagy in the treatment of Alzheimer’s, Parkinson’s and Huntington’s disease.

Autophagy Receptor AKAP11, PKA activity regulation in neurons, and psychiatric disease (schizophrenia and bipolar)

Recent human genetic study has identified AKAP11 as a significant risk gene for bipolar disorder shared with schizophrenia. Our study demonstrated AKAP11 is an autophagy receptor that mediates selective degradation of PKA inhibitory subunit R1a through autophagy. Our goal is to dissect the pathogenic mechanism whereby AKAP11 deficiency predispose to the psychiatric illness by characterizing genetic animal models and establish a novel bipolar animal model. We will test new therapeutic ideas by targeting autophagy receptor AKAP11 and PKA activity.