Taub Institute: Genomics Core
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Cell Biology & Neuroscience

Michael L. Shelanski, MD, PhD: Henry Taub Professor; Co-Director, Taub Institute for Research on Alzheimer's Disease and the Aging Brain; Senior Vice Dean for Research

Ottavio Arancio, MD, PhD: Professor of Pathology and Cell Biology and of Medicine (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Karen E. Duff, PhD: Professor of Pathology and Cell Biology (in Psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain); Deputy Director, Taub Institute for Research on Alzheimer's Disease and the Aging Brain

Lloyd A. Greene, PhD: Professor of Pathology and Cell Biology

Ulrich Hengst, PhD: Associate Professor of Pathology and Cell Biology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Tae-Wan Kim, PhD: Associate Professor of Pathology and Cell Biology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Ronald K. H. Liem, PhD: Professor of Pathology and Cell Biology

Carol M. Troy, MD, PhD: Professor of Pathology and Cell Biology and Neurology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at the Columbia University Medical Center


Michael L. Shelanski, MD, PhD

Mechanism of Memory Disruption and Synaptic Dysfunction in Alzheimer's Disease
Research in my laboratory utilizes a combination of cell culture and transgenic animal approaches in an attempt to understand why the overexpression of the amyloid precursor protein (APP) or direct application of its active peptide, A-beta, inhibits intracellular signaling in neuronal cells and leads to alterations of electrical activity, dendritic spine morphology and behavior. These results are extended with analyses of neurons taken from post-mortem Alzheimer's disease brains. In the past two years our attention has been on the PKA-CREB signaling pathway and on the role of ubiquitin c-terminal hydrolase-L1 (Uch-L1) in regulating these events. We have used both drugs and protein transduction techniques to show that A-beta induced changes, both in culture and in the animal, can be reversed by restoring these pathways to their normal "balance". Other projects involve the induction of neurogenesis in neural stem cells by A-beta raising the possibility of an endogenous repair mechanism in AD, and the analysis of the action of the ginkgolides on neuronal function. The laboratory approaches these questions with a wide range of tools including biochemistry, cell biology, physiology and microscopy.

Ottavio Arancio, MD, PhD

Mechanisms Underlying Changes of Synaptic Function Associated with Cognitive Impairment
Research in my laboratory stems from my life-long commitment to studying mechanisms of synaptic plasticity. I am interested in the cellular and molecular mechanisms that underlie long-lasting changes of synaptic function in both normal, healthy brains and in the brains of those affected by neurological disorders, in particular Alzheimer's disease (AD). Research in my laboratory has focused on the mechanisms by which amyloid-β (Aβ) peptides interfere with both memory formation and the regulation of hippocampal long-term potentiation (LTP), an activity-dependent model of synaptic plasticity that is thought to be related with learning and memory. I am interested in how regulation of gene activation and silencing, post-translational mechanisms, channel opening, intracellular calcium transients and changes in transmitter release machinery might participate in basal synaptic transmission and in synaptic plasticity. The research of my laboratory is answering the following questions:

1) How does Aβ elevation impair synaptic plasticity and memory? Experiments addressing this question examine Aβ-induced modifications in epigenetic and post-translational mechanisms.

Epigenetic mechanisms: We are exploring steps affected at the downstream level of CREB phosphorylation. CREB plays an important role together with CBP in gene transcription through histone acetylation leading to the loss of chromosomal repression and transcription of genes needed for synthesis of proteins underlying memory formation. Thus, we are investigating if reduced histone acetylation follows the reduction of CREB phosphorylation by Aβ elevation. Chromatin changes do not have to be necessarily limited to histone acetylation. As a mechanism which can "lock in" particular states of pathological gene expression in human cells, DNA methylation is an obvious candidate for contributing to the inexorably progression and irreversibility of AD in the middle to late stages of the disease. Additionally, DNA methylation may act early in AD, as some very recent work has shown that the proper regulation of gene expression in memory formation is not only controlled by the transcriptional machinery but also modulated by epigenetics. We are currently identifying genes that are differentially methylated following Aβ elevation.

Post-translational mechanisms: SUMOylation is a post-translational mechanism other than phosphorylation involving the covalent attachment of a small 11 kDA protein moiety, SUMO (Small Ubiquitin-like MOdifier), to substrate proteins. We are investigating if SUMOylation plays a role in learning and memory. We are also investigating whether it is modified following Aβ elevation and if by re-establishing normal SUMOylation one can revert synaptic and cognitive dysfunctions in AD mouse models.

2) Does Aβ play a critical positive role in synaptic plasticity and memory? Recent research performed in my laboratory has shown that low levels of Aβ similar to those present in the brains of healthy individuals throughout life, enhance LTP and memory. We are continuing these studies to explore the role of endogenous Aβ in LTP and memory. We are addressing the following questions: can we visualize release of endogenous Aβ and follow its fate in normal physiological conditions? Are changes in APP processing by the secretases or other changes in APP metabolism responsible for the increase in Aβ levels during synaptic activity? Does release of Aβ from intracellular pools account for the increase in Aβ following activity in the presynaptic terminal? Most importantly, a fundamental question originating from the discovery of a positive function for Aβ is: how does it happen that a molecule performing a positive function gains a new and negative function?

All this work would be incomplete without the goal to move each project forward to the stage where it not only provides new biological insights but also, when appropriate, serve as the basis for future development of new therapeutic strategies. Such translational research is enhanced by collaborations with medicinal-chemists, biotech specialists, pathologists and clinicians. These studies should lead to the design of novel therapeutic approaches that might be effective in preventing or delaying the onset of AD and other neurodegenerative diseases characterized by cognitive disorders.

Karen Duff, PhD

Understanding the Molecular Basis of Neurodegenerative and Neuropsychiatric Diseases

In general, we are exploring what goes wrong in the brains of patients with neurodegenerative diseases, especially Alzheimer's disease (AD) and Frontal Temporal lobe Degeneration linked to tauopathy (FTD-tau) with the overall aim of identifying therapeutic approaches that may be beneficial for the treatment, or prevention of these diseases. Given our broad interest in neurodegenerative disease etiology and the insights to be gained by studying different diseases my lab has created various mouse models for the study of AD (amyloid accumulation), tauopathies and synucleinopathies. These models have facilitated the study of many aspects of pathogenesis from how the disease propagates through the brain, to imaging studies allowing the examination of structural and functional changes in the brain in living animals, to the identification of relevant druggable pathways and the testing of drugs. Our current interests are fourfold- the propagation of disease through the brain, the impact of ApoE4 on disease risk, the impact and restoration of functional clearance mechanisms and the basis and manipulation of memory deficits using optogenetic and brain stimulation techniques.

Lloyd Greene, PhD

Neuronal Differentiation
The overall goal of research in this laboratory is to understand the mechanisms whereby neuronal precursors differentiate into mature functional neurons. To this end, we use the rat PC12 pheochromocytoma cell line developed in this laboratory as a model system to study the mechanism of action of nerve growth factor (NGF) and the steps that lead to neuronal differentiation. Among current projects in the laboratory are those addressing the following questions: 1) What is the essential property of the high-affinity NGF receptor that permits it to mediate the functional activities of NGF and how is this receptor different from the low-affinity, non-functional NGF receptor? 2) What is the transductional mechanism by which NGF receptor occupancy leads to subsequent response? 3) What are the steps beyond immediate transduction that lead to NGF mechanisms? 4) What is the mechanism by which NGF regulates growth cone motility? What are the molecules involved in this effect? 5) What genes are regulated by NGF? By what pathways are they regulated? 6) What are the mechanism by which NGF promotes the initiation and regeneration of neurites; specifically, what is the role of specific cytoskeleton proteins in this process? 7) How do NGF and other neuronotrophic substances maintain cell survival? 8) How do such agents regulate cell proliferation?

Ulrich Hengst, PhD

Local protein synthesis in developing and degenerating neurons
Neurons are arguable the cells with the most extreme morphological polarization, with distances between the periphery and the neuronal cell bodies ranging from millimeters to several feet. This extreme architectural polarization is mirrored in the existence of functionally distinct subcellular compartments, chiefly dendrites, axon, and soma. Spatially restricted protein expression is crucial for the establishment and maintenance of polarized neuronal morphology and function. Indeed, it has become apparent that alterations of polarized protein expression can cause or contribute to the pathogenesis of a wide variety of disorders. Our laboratory studies the physiological role of intra-axonal translation during development as well as the possible role of local protein synthesis during neurodegenerative disorders, especially Alzheimer's disease. We seek to understand how changes in local protein synthesis can either attenuate or ameliorate neuronal integrity in AD brain.

Tae-Wan Kim, PhD

Molecular Mechanisms and Translational Research in Alzheimer's Disease
The major goal of our laboratory is to understand the molecular basis of Alzheimer's disease (AD) using a multidisciplinary approach based on molecular, cellular and chemical biology. We are also conducting translation research aimed at discovery and pre-clinical development of novel therapies for AD. Several cellular disease models are being used, including mouse embryonic stem (ES) cell-derived neurons as an alternative to primary cortical neurons for small molecule screening and functional genetic analyses. Relevant mouse models are also being utilized.

The first theme of our research is to understand the fundamental biochemical and cellular defects associated with the familial forms of AD, which occur in a small, but significant proportion of AD cases. Although familial AD (FAD) accounts for a small percentage of all AD cases, at the neuropathological level it is phenotypically indistinguishable from the more common (sporadic) form of AD. Thus, understanding the genotype-to-phenotype transition in presenilin-dependent FAD is likely to shed light on the pathogenesis of the more common, non-familial AD. Mutations in the genes encoding the presenilins (PS1 and PS2) are the most common cause of early-onset FAD and give rise to multiple cellular deficits. It has been shown that PS1 or PS2 serve as catalytic components of the γ-secretase complex that is essential for regulated intramembrane proteolysis (RIP) of select transmembrane receptor-like substrates, including APP. At the same time, the presenilins are well-accepted as regulators of calcium and several ion channels via a γ-secretase-independent mechanism. We investigate the molecular basis for the multi-functional nature of the presenilins as regulators of both intracellular ion homeostasis and intramembrane proteolysis. Both γ-secretase-independent and dependent pathogenic mechanisms have been studied in the lab.

The second subject of our research is to identify molecular factors controlling biogenesis and synaptic action of amyloid β-peptide (A β), a pathogenic agent in AD. Our recent studies reveal that alterations in phosphatidyl-4,5-bisphosphate [known as PI(4,5)P2], a phosphoinositide lipid that controls several essential neural functions, contributes to the biochemical and cellular defects associated with AD. Specific emphasis has been given to the role of PI(4,5)P2 in amyloid β-peptide (A β)-induced impairments in synaptic plasticity (synaptic dysfunction). Synaptic dysfunction caused by A β has been linked to cognitive decline associated with AD. Molecular, physiological and mouse genetic approaches are currently being used to investigate the hypothesis that A β-induced PI(4,5)P2 breakdown is an early and critical event that precedes other A β-associated morphological and functional synaptic changes such as loss of dendritic spines and suppression of long-term potentiation (LTP). We are also addressing whether the PI(4,5)P2 pathway can be targeted for novel AD therapeutics. This project is being conducted in close collaboration with the laboratory of Dr. Gilbert Di Paolo.

The goal of third project is to understand how BACE1, one of the key enzymes responsible for A β biogenesis, is regulated in neural cells. BACE1 mediates the proteolytic cleavage of β-amyloid precursor protein (APP) and the activity/levels of BACE1 are elevated in brains of AD mouse models as well as in postmortem AD brain tissue. We have conducted a high throughput cell-based assay and identified small molecules that can modulate BACE1 function via either a direct or indirect mechanism. Using these chemical probes, our laboratory is trying to understand the mechanism of BACE1 regulation by identifying cellular target(s) of these novel chemical modulators of BACE1. Furthermore, some of the small molecule hits are being developed as therapeutic candidates for the treatment of AD. Complementary to the chemical biology approach, biochemical experiments to isolate the BACE1-haboring molecular complex have been conducted. Several BACE1-associated proteins, including members of the sorting nexin and sortilin families of protein trafficking modulators, have been identified. The function and pathological relevance of these proteins are being investigated.

Ronald Liem, PhD

The Neuronal Cytoskeleton in Neurodegenerative Diseases
Charcot-Marie-Tooth disease (CMT) is the most commonly inherited neurological disorder with a reported prevalence of 1 in 2500 people world-wide. It is found in all races and ethnic groups. CMT is slowly progressive and CMT patients suffer from degeneration of the peripheral nerves that control sensory information of the foot/leg and hand/arm. The nerve degeneration causes the subsequent degeneration of the muscles in the extremities. CMT is divided in two major types, CMT1 and CMT2. CMT1 is a demyelinating neuropathy, and due to mutations in genes important in myelin formation, whereas CMT2 is axonal. Mutations in the neuronal intermediate filament gene, NEFL have been shown to be the primary cause of CMT2. NEFL encodes the neurofilament light (NFL) protein that we have previously shown to be a necessary component for the assembly of neuronal intermediate filaments. Neuronal intermediate filaments form the intermediate filament network in neurons and are the predominant cytoskeletal structure in the axon.

Neurofilamentous aggregates both in the neuronal cell bodies and axons are seen in patients with mutations in NEFL, as well as in other neurodegenerative diseases. We have studied the NEFL mutations in transfected cells and found that in both neuronal and non-neuronal cells, mutant NFL resulted in misassembly of the intermediate filament network. This effect was dominant in agreement with the dominant nature of the NEFL mutations associated with CMT2E. In neuronal cells, we found that the mutant proteins caused defects in axonal transport leading to degeneration of neurites. Our studies showed a perfect correlation between pathogenic mutant NFL and the misassembly of filaments in the cultured cells. We are characterizing these mutations in more detail in transgenic animals. We hypothesize that inhibitors of neurofilament misassembly will lead to therapies for CMT. Our cell and animal models will be useful for screening of potential therapeutic agents against the disease.

We are also studying a family of cytoskeletal linker proteins called plakins. One of these plakins, BPAG1 was originally described as a component of the hemidesmosome in the epithelia, where it links the intermediate filaments to the extracellular matrix. Interestingly, the mutant mouse dystonia musculorum (dt), which suffers from a severe hereditary sensory neuropathy is due to mutations in the BPAG1 gene. Focal axonal swellings filled with neurofilaments, mitochondria and membrane bound dense bodies are hallmarks of the pathology of these mice and we are studying the neuronal form of this molecule. A closely related plakin called MACF1 (Microtubule actin crosslinking factor) is also highly expressed in the nervous system. MACF1-/- mice are embryonic lethal, and we have generated a neuron-specific knock-out of MACF1, which shows defects in neuronal migration. We are further characterizing this neuron-specific knock-out and also determining whether MACF1 and BPAG1 have related functions in various tissues.

Carol Troy, MD, PhD

Molecular and Cellular Specificity of Caspase Signaling Pathways
The work in my laboratory stems from my long-standing interest in understanding the molecular specificity of death pathways. Throughout the body there is homeostasis of life and death at the cellular level. In disease where death is dysregulated in particular cells there are alterations in the affected cells but not throughout the body. Neuronal degeneration and death are the hallmarks of many neurological diseases, including Alzheimer’s Disease, Parkinson’s Disease and stroke, and there is considerable evidence that caspases play a critical role in the progression of these diseases. Thus we need to identify specific targets that are altered in the disease state but are not required for normal cellular homeostasis. In our lab we focus on the regulation and function of the caspase family of proteases in the developing and mature nervous system. Best known as the executors of cell death, there is increasing appreciation that some caspases may also have non-apoptotic functions. Individual caspases cleave specific substrates at one or two cleavage sites. Cleavage can result in inactivation of a substrate, a change in the substrates activity, or target the substrate for ubiquitination and degradation. However, caspase cleavage of a substrate on its own does not degrade the cellular proteins. This positions aberrant caspase activity as a potential therapeutic target. To study caspase pathways we have developed molecular tools that allow the study of individual members of protein families in the normal nervous system and in disease. We utilize in vivo and in vitro models to study both molecular pathways and therapeutic interventions. Current work includes mouse lines with cell specific deletion of individual caspases to determine the cell specific functions of these proteins in the developing and adult nervous system.


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