Cell Biology of Nerve Cells neuron

  The Zheng lab studies the cell biology of neurons. We specifically focus on the signal transduction and cytoskeletal mechanisms underlying neural development, disorders, and regeneration. Three major areas are being pursued in our lab: (1) axonal growth and guidance, (2) synapse formation and plasticity, and (3) intracellular trafficking. Our research employs some unique experimental approaches that combine sophisticated molecular/cellular imaging and powerful molecular manipulation to perform functional analyses of neurons at single molecule level. Our goal is to not only gain a mechanistic understanding of the molecular and cellular aspects of neuronal structure and function, but also provide insights into the cellular basis for brain abnormality and disorders. It is our hope that these basic studies will build the foundation for the development of potential strategies and treatments to promote regeneration and repair of damaged neuronal circuitry after neural injuries and degeneration.

1. Axonal Growth, Guidance, and Regeneration

Nerve Growth Cone   Over a century ago, Ramn y Cajal made his landmark observations on the patterns of nerve process outgrowth and connectivity in developing brains and described the motile tip of each elongating axon, the growth cone, as the responsible unit for axon elongation and pathfinding to the target cells. Developing axons are guided to their targets by a variety of environmental cues, including long-range diffusible and short-range surface-bound molecules that can either attract or repel the axon. The presence of these guidance cues in temporal and spatial patterns enables the growth cone to navigate through the complex environment of the developing embryo to reach its correct target. We investigate the signaling pathways and cytoskeletal mechanisms that enable the growth cone to translate extracellular signals to directional movement during guidance. Our research focuses on three cellular levels: At the membrane level, we study microdomains in spatiotemporal signal transduction of extracellular cues during guidance. At the intracellular level, our efforts are to elucidate intricate signaling cascades (e.g. Ca2+ pathway) that translate extracellular cues to directed axonal growth. Different signaling pathways are likely to interact and eventually converge on the cytoskeleton for directed growth cone movement. The third line of research in the lab investigates the cytoskeletal mechanisms underlying growth cone extension and guidance. The lack of axon regeneration of the adult central nervous system is in part due to the presence of inhibitory molecules at the injury site, including myelin associated proteins (e.g. MAG and Nogo). Our work on the signaling and cytoskeletal mechanisms in developing axons could potentially provide means to overcome inhibitory signals for promoting axon regeneration after nerve injury. In summary, we are pursuing a line of research aiming to elucidate the mechanistic links between extracellular factors and directional motility of axonal growth cones, hoping to identify the targets for promoting adult axon regeneration.

2. Synapse Formation and Plasticity

A CA3 neuron in hippocampal slice - live imaging   Synapses represent the basic unit of neuronal communications and most of the excitatory synapses reside on dendritic spines, a type of dendritic protrusions that host neurotransmitter receptors and other postsynaptic specializations. Synapses are plastic and undergo short- and long-term modifications during developmental refinement of neuronal circuitry, as well as during learning and memory. Synaptic modifications involve both pre- and post-synaptic changes. Postsynaptically, modifications of the surface neurotransmitter receptors (numbers and properties) are believed to be a key event underlying the changes in synaptic strength. In addition, dendritic spines undergo rapid changes in shape and size in association with synaptic modifications. Our lab is interested in the cytoskeletal mechanisms that underlie the spine development during synaptogenesis and postsynaptic modifications during synaptic plasticity. In particular, we have been studying the role of microtubules and the actin dynamics in spine formation, dynamics, and synaptic receptor trafficking. Since many neurological disorders have been associated with alterations in synaptic connections, we hope that our study will also shed light on brain development and functions under both physiological and pathological conditions.

3. Intracellular trafficking and neurodegenerative diseases

Live imaging of spines   Trafficking of proteins and organelles to different subcellular locations in neurons is essential for proper neuronal functions. Many neurodegenerative diseases, e.g. Alzheimer's, Huntington, and Parkinson diseases, involve impairment in neuronal trafficking. We study the cell biology of intracellular trafficking of organelles and receptors during normal neuronal functions and under influence of disease-associated molecules. For example, Alzheimer's disease (AD) is a progressive neurodegenerative disease highlighted by two pathological hallmarks: extracellular senile plaques containing amyloid (A) fibrils and intracellular neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated tau proteins. Recent studies indicate that soluble A oligomers exhibit severe inhibition of synaptic functions and plasticity, indicating that these intermediate A aggregates, not the fibrils, may be responsible for synaptic deficits in AD brains. We find that soluble A molecules can acutely impair fast transport of mitochondria through a specific signaling pathway involving GSK3. We further found that A oligomers impair AMPA receptor trafficking during synaptic plasticity. The central hypothesis to be tested in the lab is that A oligomers exhibit acute inhibition on neuronal trafficking, which may constitute one of the early A adverse effects leading to the disruption of normal neuronal functions and development of AD-related neuronal dysfunctions. We are performing a series of experiments to test this hypothesis and to elucidate the underlying mechanisms.

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