ZhenyuYue_

Molecular and Cellular Mechanisms of Neurological Disorders and Therapeutic Development

The Yue Laboratory focuses on investigating the molecular, cellular, network, circuitry, and behavioral mechanisms underlying various neurological disorders and psychiatric conditions, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, bipolar disorder, and schizophrenia. The Yue lab employs a multidisciplinary approach, utilizing experimental and bioinformatic methods to gain insights into the pathogenesis of these disorders and to develop potential therapeutic strategies.

1. Disease Mechanisms: We focus on cellular processes such as autophagy-lysosome degradation, synaptic vesicle trafficking and activity, cellular metabolism, neuroinflammation, and protein/lipid kinase signaling.

2. Experimental Techniques: Mouse genetics, biochemical assays, molecular and cellular biology approaches, primary neuron/glia cultures, cellular imaging (both live and fixed), transcriptomics (including single-cell RNA sequencing and spatial transcriptomics), proteomics, bioinformatics, and animal pathology/behavioral studies.

3. Human-Relevant Models: Human-induced pluripotent stem cell (iPSC)-derived neurons and glia (2D and 3D), postmortem tissue analysis

4. Translational Research: Therapeutic target identification and validation, disease modification development focused on nanobody, gene therapy, and drug repositioning.

Pathogenic mechanism of neuron and glia interactions in Parkinson’s disease

We are undertaking the profiling and characterization of molecularly distinct subtypes of neurons and glia in the substantia nigra pars compacta (SNpc) from Parkinson’s disease (PD) brains. Our goal is to identify novel cell types and unravel the molecular mechanisms underlying the vulnerability and resilience of neurons in PD. We employ a multidisciplinary approach, integrating network modeling with experimental validation using human postmortem tissues, genetic mouse models, and induced human neurons (iPSC) in both 2D and 3D midbrain cultures. We aim to model and characterize human dopamine neuron subpopulations, pinpointing those associated with PD vulnerability within the SNpc, utilizing hiPSC-based models. See our PD Center website: https://icahn.mssm.edu/research/center-parkinsons-disease

Molecular mechanism of 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 alpha-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 alpha-synuclein; (2) LRRK2 acts as an interface for the signaling pathways that leads to PD and 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.

Microglial autophagy and cellular senescence in Alzheimer’s disease and Parkinson’s disease

Autophagy represents an evolutionarily conserved lysosomal degradation system crucial for cellular homeostasis. Its regulation varies across cell types and is intricately linked to the pathogenic pathways of neurodegenerative diseases. Our research endeavors aim to elucidate the neuroprotective mechanisms conferred by autophagy in microglia and to comprehend how dysfunctional autophagy in microglia contributes to cellular senescence and the pathogenesis of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Our central hypothesis posits that cellular senescence is accelerated in microglia in the AD and PD brains. Through our investigations, we seek to delineate the role of microglial autophagy in modulating inflammation and curtailing senescence via selective degradation processes. Our ultimate goal is to devise therapeutic strategies geared towards the removal of senescent microglia to foster neuroprotection during both aging and the progression of neurodegenerative diseases.

Autophagy-lysosome dysfunctions in neurons and glial cells in the pathogenesis of neurodegenerative diseases

We propose to elucidate the cell-type-specific autophagy-lysosome pathways, focusing on neurons and microglia, under both physiological (young and old) and pathological conditions (Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease). Employing a systematic approach, we will incorporate multiple genetic mutant lines of mice, human-induced neuron lines (hiN), quantitative proteomics, and molecular and cell biology techniques to identify autophagy cargo and receptors in neurons and microglia. Furthermore, we will investigate the distinct mechanisms responsible for the degradation of multiple disease-associated proteins such as tau, alpha-synuclein (aSyn), and huntingtin. The findings of our study hold the potential to uncover novel biomarkers and therapeutic targets for autophagy-lysosomes in the treatment of Alzheimer’s, Parkinson’s, and Huntington’s diseases, thereby paving the way for innovative therapeutic interventions.

Dysfunctional AKAP11-PKA signaling underlying the pathogenic mechanism and in modeling psychiatric disease condition (schizophrenia and bipolar)

Recent human genetic study has identified AKAP11 as a definitive causal gene for bipolar disorder and enhanced risk factor for schizophrenia. Our study demonstrated AKAP11 is an autophagy receptor that mediates selective degradation of PKA-RI complex through autophagy. Our goal is to dissect the pathogenic mechanism whereby AKAP11 deficiency contributes to the psychiatric illness by characterizing genetic animal models and induced human neuron (iNeuron) models. We will test the new therapeutic ideas by targeting AKAP11-PKA signaling and activity.