Scott Michael Wilson
University Of Alabama At Birmingham
Project start date: 2004-01-01
Project end date: 2014-12-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Scott Michael Wilson
The Role Of Usp14 In Regulating Neuronal Function
Scott Michael Wilson, Assistant Professor
University Of Alabama At Birmingham 1530 3rd Avenue South Birmingham, Al 35294
Grant 5R01NS047533-04 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: The ubiquitin-proteasome system (UPS) is a central pathway common to all eukaryotic cells for regulating protein turnover. There are numerous regulatory pathways that rely on the timely removal of critical proteins. These pathways include the cell cycle, DNA repair, receptor-mediated endocytosis and the induction of long-term memory. The inability to remove unwanted proteins from cells has been linked to several chronic neurological diseases including Parkinson s disease, Alzheimer s disease, and the Spinocerebellar ataxias. While it is clear that these diseases are associated with polyubiquitinated protein aggregates, it is not clear how these aggregates contribute to neuronal dysfunction. In contrast to the polyubiquitination signal that targets proteins for proteasomal degradation, a monoubiquintin tag can signal receptor internalization and sorting of intracellular vesicles. This modification by monoubiquitin is reversible and, akin to phosphorylation, can regulate protein localization and activity. We have recently demonstrated that Uspl4, a deubiquitinating enzyme (DUB) that specifically removes ubiquitin from proteins, is mutated in the neurological mouse mutant ataxia (ax/j). The axJ mice do not show protein aggregation defects or neuronal loss. Instead, these mice exhibit defects in synaptic transmission, indicating that neurological disease may be rooted in synaptic dysfunction. Our working hypothesis is that loss of Uspl4 disrupts the ubiquitinated state of specific components of the neurotransmitter release machinery, thereby resulting in synaptic defects. This proposal is therefore directed at addressing the role of Uspl4 in regulating synaptic function. The first Aim will determine if Usp 14 associates with the 26S proteasome in neurons and if it has a role in ubiquitin-dependent proteolysis. In the second Aim, we will identify components and pathways that are regulated by Usp14 in order to better understand the regulation of ubiquitin modification in normal physiology and disease. The third Specific Aim will determine which neuronal circuits are disrupted by the loss of Uspl4 and examine how these circuits contribute to the tremor, ataxia and muscle wasting phenotypes of the ax J mice. Completion of these Specific Aims will enable us to uncover new processes that rely on ubiquitin-signaling and to determine how alterations in these pathways can lead to neurological disease.
Keywords: endopeptidase, neurotransmitter transport, protein structure function, synapse, ubiquitin, ataxia, cerebellar Purkinje cell, enzyme substrate, granule cell, muscle disorder, neuroanatomy, neuron, phenotype, proteasome, protein protein interaction, proteolysis, tremor, genetically modified animal, immunoprecipitation, laboratory mouse
Project start date: 2004-01-01
Project end date: 2008-12-31
5R01NS047533-04 (2007): $286143
ALABAMA NEUROSCIENCE BLUEPRINT CORE CENTER
Scott Michael Wilson
University Of Alabama At Birmingham, 1530 3rd Avenue South, Birmingham, Al 35294
Abstract: Neuroscience is one of the most important areas of modern biomedical research. Despite the declaration of the 1990´s as the "Decade of the Brain" and significant scientific advances over the last 15 years, effective treatments for neurological and psychiatric diseases remains the largest and fastest growing unmet medical need in the United States. To meet this need, a multi-disciplinary and integrative approach to neuroscience research is essential. Faithful small animal models of human neurological and psychiatric function and dysfunction must be developed and capitalized upon to enhance our understanding of the nervous system and to aid the development of new disease prevention and treatment strategies. The University of Alabama at Birmingham (UAB) has a long history of establishing and supporting thematic cores and centers and as part of a recently completed UAB School of Medicine Strategic Planning process, the development of a truly innovative and interdisciplinary Comprehensive Neuroscience Center has been identified as a top institutional priority. UAB has experienced a dramatic influx of accomplished neuroscience investigators in numerous departments over the last several years and has committed substantial resources to the recruitment of both junior and senior level neuroscience investigators over the next five years. In this application we propose to establish a series of inter-related core facilities that will facilitate ongoing studies of genetically modified rodents and other small animals and enhance future generation, characterization, and mechanistic analyses of small animal models of neurological and psychiatric function and dysfunction. In addition to an Administrative Core (Core A), five new research cores will be established Core B, Molecular Engineering; Core C, Cellular and Molecular Neuropathology; Core D, Neuroimaging; Core E, In Vivo Physiology & Phenotyping; and Core F, Cellular and Synaptic Physiology. These cores are specifically designed to provide new research capabilities and will complement existing facilities to provide neuroscience investigators unparalleled ability to develop and study unique animal models of neurobiology and neuropathology. In addition to the large neuroscience community at UAB, the Alabama Neuroscience Blueprint Core Center will support the research activities of Neuroscience Blueprint funded investigators throughout the State of Alabama and at institutions in neighboring states. Combined with ongoing efforts to establish a Comprehensive Neuroscience Center at UAB, this application will dramatically enhance neuroscience research capabilities in the Deep South. Finally, a major goal of this application is to provide junior investigators and previously funded Blueprint Institute and Center neuroscientists a mechanism by which they can be scientifically productive during an exceedingly tight NIH budget period
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
5P30NS057098-05_9002 (2010): $222257
5P30NS057098-04_9002 (2009): $215782
THE ROLE OF USP 14 IN REGULATING NEURONAL FUNCTION
Scott Michael Wilson, Assistant Professor
University Of Alabama At Birmingham, 1530 3rd Avenue South, Birmingham, Al 35294
Grant 2R01NS047533-06A2 from National Institute Of Neurological Disorders And Stroke
Abstract: Alterations in the neuromuscular junction (NMJ) have recently been reported in motor neuron diseases such as Spinal muscular atrophy (SMA); however, little is known about the pathways that regulate synaptic activity and development in motor neurons. Although transcriptional mechanisms have been shown to regulate critical steps in the development of the nervous system, recent studies have highlighted the importance of the ubiquitin proteasome system (UPS) in the development and maintenance of synaptic connections. By regulating ubiquitin signaling pathways, such as kinase activation and the trafficking and abundance of cellular proteins, the UPS can control developmental transition points during the maturation of the nervous system. However, it is not known how the cell regulates available ubiquitin pools required for these processes. Given the distance that separates the motor neuron cell body and endplate, specialized mechanisms must ensure the stable expression of ubiquitin necessary for axon path finding, synaptic targeting and motor endplate maturation. Our studies now demonstrate that the proteasomal deubiquitinating enzyme Usp14 is required for the postnatal development of the motor neuron endplate. Homozygous axJ mice, which are deficient for Usp14, display a resting tremor, hind limb rigidity, reduced muscle mass and die by 8 weeks of age. These mice do not have ubiquitinated protein aggregates or accelerated neuronal cell death, but instead show ubiquitin loss that correlates with impaired motor endplate maturation during the first two weeks of postnatal development. Restoration of ubiquitin levels in the axJ mice increases body mass and motor function and prevents postnatal lethality, indicating that ubiquitin loss can be a major contributor to neuromuscular disease. Our recent studies also demonstrate ubiquitin loss in a mouse model of SMA, which displays impaired NMJ maturation and function similar to the axJ mice, validating the importance of identifying the developmental pathways regulated by ubiquitin. Our working hypothesis is that Usp14 functions to maintain ubiquitin levels required for the development and activity of mammalian synapses. The first aim of this proposal will determine the contribution of ubiquitin loss in the axJ mice to the development and activity of the NMJ. In the second aim, we will investigate a newly proposed catalytic-independent function of Usp14 on the proteasome and determine if it is required for development and synaptic transmission at the NMJ. The third aim is designed to determine the role of motor neurons and motor endplates in the disease process in the axJ mice. The final aim will examine the ubiquitin-dependent pathways that control synaptic maturation and function of the NMJ. This proposal will use a combination of genetics and biochemistry to investigate the essential enzymatic functions of Usp14 on the proteasome and determine how changes in the activity of Usp14 alter signaling pathways required for synaptic development and function. The ubiquitin proteasome system functions to control cellular pathways by regulating protein levels within cells. Since alterations in protein turnover are believed to be central to several chronic neurological diseases, the identification and analysis of components of the ubiquitin proteasome system will provide new insights into the mechanisms of neurological disease and identify potential targets for therapeutic intervention
Keywords: 20S Catalytic Proteasome; 20S Core Proteasome; 20S Proteasome; 20S Proteosome; ALS; APF-1; ATP-Dependent Proteolysis Factor 1; Acute; Address; Affect; Age; Amyotrophic Lateral Sclerosis; Aran-Duchenne disease; Axon; Axon Terminals; Behavioral; Biochemistry; Cell Communication and Signaling; Cell Culture Techniques; Cell Signaling; Cells; Cessation of life; Chemistry, Biological; Chronic; Cruveilhier disease; Cues; Data; Death; Defect; Deubiquitinating Enzyme; Deubiquitination; Development; Disease; Disorder; EC 2.7; Ensure; Extracellular Signal-Regulated Kinase Gene; Extremities; Figs; Figs - dietary; Gehrig`s Disease; Genetic; Genetic Alteration; Genetic Change; Genetic defect; HMG-20; High Mobility Protein 20; Hydrolase; Hydrolysis; Intracellular Communication and Signaling; Ion Channels, Sodium; Kinases; Lead; Limb structure; Limbs; Lou Gehrig Disease; MAP Kinase Gene; MAPK; Macropain; Macroxyproteinase; Maintenance; Maintenances; Mammals, Mice; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase Gene; Motor; Motor Cell; Motor End-Plate; Motor Endplate; Motor Neuron Disease; Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Motor Neurons; Multicatalytic Proteinase; Murine; Mus; Muscle Rigidity; Mutation; Myoneural Junction; NRVS-SYS; Nerve; Nerve Cells; Nerve Endings, Presynaptic; Nerve Impulse Transmission; Nerve Transmission; Nerve Unit; Nervous; Nervous System; Nervous System Diseases; Nervous system structure; Neural Cell; Neural Transmission; Neurocyte; Neurologic; Neurologic Body System; Neurologic Disorders; Neurologic Organ System; Neurological; Neurological Disorders; Neuromuscular Diseases; Neuromuscular Junction; Neuronal Transmission; Neurons; Non-Trunk; Pathogenesis; Pathology; Pathway interactions; Pb element; Phenotype; Phosphotransferases; Presynaptic Terminals; Process; Prosome; Proteasome; Proteasome Endopeptidase Complex; Protein Degradation, Metabolic; Protein Degradation, Regulatory; Protein Turnover; Proteins; Proteosome; Publishing; Recycling; Regulation; Reporting; Research; Rest Tremor; Rigidity; Rigidity, Muscular; Role; Series; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Site; Sodium Channel; Spinal Muscular Atrophy; Synapses; Synaptic; Synaptic Boutons; Synaptic Terminals; Synaptic Transmission; System; System, LOINC Axis 4; Testing; Therapeutic Intervention; Transgenes; Transgenic Mice; Transgenic Organisms; Transphosphorylases; Ubiquitin; V (voltage); Work; Yeasts; biological signal transduction; design; designing; disease/disorder; effective therapy; experiment; experimental research; experimental study; gene product; genome mutation; heavy metal Pb; heavy metal lead; in vivo; inhibitor; inhibitor/antagonist; insight; insoluble aggregate; intervention development; intervention therapy; motoneuron; motor neuron development; motor neuron function; mouse model; multicatalytic endopeptidase complex; muscle form; mutant; myoneural disorder; nervous system development; nervous system disorder; neurofilament; neurological disease; neuromuscular disorder; neuron cell death; neuron development; neuron loss; neuronal; neuronal cell death; neuronal loss; neurotransmission; pathway; postnatal; prevent; preventing; protein aggregate; protein degradation; public health relevance; research study; response; restoration; small molecule; social role; synapse failure; synapse function; synaptic failure; synaptic function; therapy development; trafficking; transgenic; treatment development; voltage
Relevance: Narrative The ubiquitin proteasome system functions to control cellular pathways by regulating protein levels within cells. Since alterations in protein turnover are believed to be central to several chronic neurological diseases, the identification and analysis of components of the ubiquitin proteasome system will provide new insights into the mechanisms of neurological disease and identify potential targets for therapeutic intervention
Project start date: 2004-01-01
Project end date: 2014-12-31
Budget start date: 1-FEB-2010
Budget end date: 31-DEC-2010
PFA/PA: PA-07-070
2R01NS047533-06A2 (2010): $320469
Scott Michael Wilson
University Of Alabama At Birmingham
Project start date: 2004-01-01
Project end date: 2014-12-31
Alabama Neuroscience Blueprint Core Center
Scott Michael Wilson, Assistant Professor
University Of Alabama At Birmingham 1530 3rd Avenue South Birmingham, Al 35294
Grant 5P30NS057098-029002 from National Institute Of Neurological Disorders And Stroke IRG: ZNS1
Keywords: model