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The Basis Of Vcp-Mediated Degeneration: Insights From A Drosophila Model Of Disease, Gillian P. Ritson 2010 University of Pennsylvania

The Basis Of Vcp-Mediated Degeneration: Insights From A Drosophila Model Of Disease, Gillian P. Ritson

Publicly Accessible Penn Dissertations

Valosin-containing protein (VCP) is a highly conserved molecular chaperone that regulates a wide array of essential cellular processes. Mutations in VCP are causative of degenerative disease that can affect muscle, brain and bone. Despite VCP being implicated in many major pathways in the cell, the mechanism of disease pathogenesis is unknown. To gain insight into the degeneration associated with mutations in VCP, we developed and characterized a Drosophila model of disease that recapitulated VCP mutation-dependent toxicity. VCP is involved in a diverse array of activities, many of which we may not know. Therefore we employed an unbiased genetic screening method ...


Huntingtin Cleavage Product A Forms In Neurons And Is Reduced By Gamma-Secretase Inhibitors, Kimberly B. Kegel, Ellen Sapp, Jonathan Alexander, Patrick Reeves, Dorothee Bleckmann, Linsday Sobin, Nicholas Masso, Antonio Valencia, Hyunkyung Jeong, Dimitri Krainc, James Palacino, Daniel Curtis, Rainer Kuhn, Claudia Betschart, Miguel Sena-Esteves, Neil Aronin, Paolo Paganetti, Marian DiFiglia 2010 Massachusetts General Hospital

Huntingtin Cleavage Product A Forms In Neurons And Is Reduced By Gamma-Secretase Inhibitors, Kimberly B. Kegel, Ellen Sapp, Jonathan Alexander, Patrick Reeves, Dorothee Bleckmann, Linsday Sobin, Nicholas Masso, Antonio Valencia, Hyunkyung Jeong, Dimitri Krainc, James Palacino, Daniel Curtis, Rainer Kuhn, Claudia Betschart, Miguel Sena-Esteves, Neil Aronin, Paolo Paganetti, Marian Difiglia

Open Access Articles

BACKGROUND: The mutation in Huntington's disease is a polyglutamine expansion near the N-terminus of huntingtin. Huntingtin expressed in immortalized neurons is cleaved near the N-terminus to form N-terminal polypeptides known as cleavage products A and B (cpA and cpB). CpA and cpB with polyglutamine expansion form inclusions in the nucleus and cytoplasm, respectively. The formation of cpA and cpB in primary neurons has not been established and the proteases involved in the formation of these fragments are unknown.

RESULTS: Delivery of htt cDNA into the mouse striatum using adeno-associated virus or into primary cortical neurons using lentivirus generated cpA ...


Regulation Of Akt And Wnt Signalling By The Dopamine D2 Receptor And Metabotropic Glutamate Receptor 2/3, Laurie P. Sutton 2010 The University of Western Ontario

Regulation Of Akt And Wnt Signalling By The Dopamine D2 Receptor And Metabotropic Glutamate Receptor 2/3, Laurie P. Sutton

Electronic Thesis and Dissertation Repository

Akt and the Wnt pathway, two cascades that regulate GSK-3, have been implicated in schizophrenia and antipsychotic drug action. Although it is known that antipsychotic drugs alleviate psychosis by blocking the dopamine D2 receptor (D2DR) and that metabotropic glutamate receptor 2/3 (mGluR2/3) agonists may improve some of the symptoms of schizophrenia, it is unclear if both classes of drugs exert their effects through Akt, GSK-3 and/or the Wnt pathway or if changes in these pathways are mediated through the D2DR and mGluR2/3 respectively. In addition to antipsychotics, mood stabilizers and antidepressants also target GSK-3, suggesting that ...


Characterizing And Treating The Neuropathology Of Tuberous Sclerosis Complex In The Mouse, Sharon W. Way 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Characterizing And Treating The Neuropathology Of Tuberous Sclerosis Complex In The Mouse, Sharon W. Way

UT GSBS Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder affecting approximately 1 in 6000 births. Developmental brain abnormalities cause substantial morbidity and mortality and often lead to neurological disease including epilepsy, cognitive disabilities, and autism. TSC is caused by inactivating mutations in either TSC1 or TSC2, whose protein products are known inhibitors of mTORC1, an important kinase regulating translation and cell growth. Nonetheless, neither the pathophysiology of the neurological manifestations of TSC nor the extent of mTORC1 involvement in the development of these lesions is known. Murine models would greatly advance the study of this debilitating disorder. This thesis ...


Hippocampal C-Jun-N-Terminal Kinases Serve As Negative Regulators Of Associative Learning, Tessi Sherrin, Thomas Blank, Cathrin Hippel, Martin Rayner, Roger J. Davis, Cedomir Todorovic 2010 University of Hawaii

Hippocampal C-Jun-N-Terminal Kinases Serve As Negative Regulators Of Associative Learning, Tessi Sherrin, Thomas Blank, Cathrin Hippel, Martin Rayner, Roger J. Davis, Cedomir Todorovic

Davis Lab Publications

In the adult mouse, signaling through c-Jun N-terminal kinases (JNKs) links exposure to acute stress to various physiological responses. Inflammatory cytokines, brain injury and ischemic insult, or exposure to psychological acute stressors induce activation of hippocampal JNKs. Here we report that exposure to acute stress caused activation of JNKs in the hippocampal CA1 and CA3 subfields, and impaired contextual fear conditioning. Conversely, intrahippocampal injection of JNKs inhibitors sp600125 (30 mum) or D-JNKI1 (8 mum) reduced activity of hippocampal JNKs and rescued stress-induced deficits in contextual fear. In addition, intrahippocampal administration of anisomycin (100 mug/mul), a potent JNKs activator, mimicked ...


Fibrinolytic Proteins And Brain-Derived Neurotrophic Factor Modulation Of Suprachiasmatic Nucleus Circadian Clock, Xiang Mou 2010 University of Tennessee - Knoxville

Fibrinolytic Proteins And Brain-Derived Neurotrophic Factor Modulation Of Suprachiasmatic Nucleus Circadian Clock, Xiang Mou

Doctoral Dissertations

Mammalian circadian rhythms are controlled by a clock located in the suprachiasmatic nucleus (SCN). The mechanisms through which light phase-shifts the SCN circadian clock are similar to those underlying memory formation and long-term potentiation (LTP). Several secreted proteins, including tissue-type plasminogen activator (tPA), plasminogen, and brain-derived neurotrophic factor (BDNF), have been implicated in this process. These same proteins are important for photic phase-shifts of the SCN circadian clock. Early night glutamate application to SCN containing brain slices resets the circadian clock. Our experiments find that the endogenous tPA inhibitor, plasminogen activator inhibitor 1(PAI-1), blocked these shifts in slices from ...


Presenilin Is Necessary For The Function Of Cbp In The Adult Drosophila Cns, Randy S. Boyles 2010 University of Nevada, Las Vegas

Presenilin Is Necessary For The Function Of Cbp In The Adult Drosophila Cns, Randy S. Boyles

UNLV Theses, Dissertations, Professional Papers, and Capstones

Dominant mutations in Presenilin (Psn) have been correlated with the formation of Aß- containing plaques in patients with inherited forms of Alzheimer's disease (AD). However, a clear mechanism directly linking amyloid plaques to the pathology of familial or sporadic forms of AD has remained elusive. Thus, recent discoveries of several new substrates for Psn protease activity have sparked alternative hypotheses to explain the preclinical symptoms of AD. CBP (CREB-binding protein) is a haplo- insufficient transcriptional co-activator with histone acetyltransferase (HAT) activity that has been proposed to be a downstream target for Psn signaling. Individuals with reduced CBP levels have ...


Distinct Roles Of C-Jun N-Terminal Kinase Isoforms In Neurite Initiation And Elongation During Axonal Regeneration, Monia Barnat, Herve Enslen, Friedrich Propst, Roger J. Davis, Sylvia Soares, Fatiha Nothias 2010 Université Pierre et Marie Curie

Distinct Roles Of C-Jun N-Terminal Kinase Isoforms In Neurite Initiation And Elongation During Axonal Regeneration, Monia Barnat, Herve Enslen, Friedrich Propst, Roger J. Davis, Sylvia Soares, Fatiha Nothias

Davis Lab Publications

c-Jun N-terminal kinases (JNKs) (comprising JNK1-3 isoforms) are members of the MAPK (mitogen-activated protein kinase) family, activated in response to various stimuli including growth factors and inflammatory cytokines. Their activation is facilitated by scaffold proteins, notably JNK-interacting protein-1 (JIP1). Originally considered to be mediators of neuronal degeneration in response to stress and injury, recent studies support a role of JNKs in early stages of neurite outgrowth, including adult axonal regeneration. However, the function of individual JNK isoforms, and their potential effector molecules, remained unknown. Here, we analyzed the role of JNK signaling during axonal regeneration from adult mouse dorsal root ...


Structural, Biochemical, And Cell Biological Characterization Of Rab7 Mutants That Cause Peripheral Neuropathy, Brett A. McCray 2010 University of Pennsylvania

Structural, Biochemical, And Cell Biological Characterization Of Rab7 Mutants That Cause Peripheral Neuropathy, Brett A. Mccray

Publicly Accessible Penn Dissertations

Coordinated trafficking of intracellular vesicles is of critical importance for the maintenance of cellular health and homeostasis. Members of the Rab GTPase family serve as master regulators of vesicular trafficking, maturation, and fusion by reversibly associating with distinct target membranes and recruiting specific effector proteins. Rabs act as molecular switches by cycling between an active, GTP-bound form and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins such as guanine nucleotide exchange factors and GTPase activating proteins. Rab7 specifically regulates the trafficking and maturation of vesicle populations that are involved ...


Studies Of Dj-1, Parkin And Alpha-Synuclein Give Insights Into Plausible Mechanisms For Parkinson's Disease Pathogenesis., Chenere P. Ramsey 2010 University of Pennsylvania

Studies Of Dj-1, Parkin And Alpha-Synuclein Give Insights Into Plausible Mechanisms For Parkinson's Disease Pathogenesis., Chenere P. Ramsey

Publicly Accessible Penn Dissertations

Parkinson’s disease (PD) is an insidious neurodegenerative disorder characterized by a range of motor symptoms which develop predominantly as a consequence of striatal dopamine depletion. The majority of PD cases are idiopathic; however, discoveries of genetic mutations linked to familial forms of PD, including mutations in the genes encoding DJ-1, parkin, and α-synuclein (α-syn), have provided insights into sporadic PD pathogenesis.

Mutations in the gene encoding DJ-1 cause autosomal recessive early-onset PD (AREP). Though the physiological role for DJ-1 is not fully elucidated, it is thought that DJ-1 mutations contribute to disease as a consequence of a loss-of-function. Herein ...


Dopaminergic Innervation Of The Subventricular Zone In The Murine Brain, Linda Beth Drozdowicz 2010 University of Connecticut - Storrs

Dopaminergic Innervation Of The Subventricular Zone In The Murine Brain, Linda Beth Drozdowicz

Honors Scholar Theses

The subventricular zone (SVZ) is one of two areas in the brain that, in a healthy mouse, continually generate neurons throughout adulthood. While it was previously thought that only the A9 neurons of the substantia nigra sent dopaminergic afferents to the SVZ, recent studies suggest that the A10 neurons of the ventral tegmental area may innervate this area. This project has aimed to discover which, if either, model is correct.

Examination of the Aphakia (AK) mouse was used to determine the role of distinct midbrain regions in SVZ regulation. Additionally, intraperitoneal injections of the chemical MPTP were used to deduce ...


Damage-Induced Inflammation And Nociceptive Hypersensitivity In Drosophila Larvae, Daniel T. Babcock 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Damage-Induced Inflammation And Nociceptive Hypersensitivity In Drosophila Larvae, Daniel T. Babcock

UT GSBS Dissertations and Theses (Open Access)

Mounting an effective response to tissue damage requires a concerted effort from a number of systems, including both the immune and nervous systems. Immune-responsive blood cells fight infection and clear debris from damaged tissues, and specialized pain receptors become hypersensitive to promote behavior that protects the damaged area while it heals. To uncover the cellular and molecular mechanisms underlying these processes, we have developed a genetically tractable invertebrate model of damage-induced inflammation and pain hypersensitivity using Drosophila larvae.

To study wound-induced inflammation, we generated transgenic larvae with fluorescent epidermal cells and blood cells (hemocytes). Using live imaging, we monitored the ...


Protein-Protein Interactions That Regulate Neurotransmitter Release From Retinal Ribbon Synapses, (Leigh) Beth T. Latham 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Protein-Protein Interactions That Regulate Neurotransmitter Release From Retinal Ribbon Synapses, (Leigh) Beth T. Latham

UT GSBS Dissertations and Theses (Open Access)

Protein-Protein Interactions That Regulate Neurotransmitter Release from Retinal Ribbon Synapses Photoreceptors and bipolar cells in the retina form specialized chemical synapses called ribbon synapses. This type of synapse differs physiologically from “conventional” chemical synapses. While “conventional” synapses exocytose neurotransmitter-filled vesicles in an all-or-none fashion in response to an action potential, a retinal ribbon synapse can release neurotransmitter tonically (sustained) in response to graded changes in membrane potential or phasically (transient) in response to a large change in membrane potential.

Synaptic vesicle exocytosis is a tightly controlled process involving many protein-protein interactions. Therefore, it is likely that the dissimilarity in the ...


The Expression And Cellular Localization Of Cc-Chemokine Receptor 5 (Ccr5) After Traumatic Brain Injury, Vuvi H. Nguyen 2010 University of Texas Graduate School of Biomedical Sciences at Houston

The Expression And Cellular Localization Of Cc-Chemokine Receptor 5 (Ccr5) After Traumatic Brain Injury, Vuvi H. Nguyen

UT GSBS Dissertations and Theses (Open Access)

Traumatic brain injury results from a primary insult and secondary events that together result in tissue injury. This primary injury occurs at the moment of impact and damage can include scalp laceration, skull fraction, cerebral contusions and lacerations as well as intracranial hemorrhage. Following the initial insult, a delayed response occurs and is characterized by hypoxia, ischemia, cerebral edema, and infection. During secondary brain injury, a series of neuroinflammatory events are triggered that can produce additional damage but may also help to protect nervous tissue from invading pathogens and help to repair the damaged tissue. Brain microglia and astrocytes become ...


The Expression And Cellular Localization Of Cc-Chemokine Receptor 5 (Ccr5) After Traumatic Brain Injury, Vuvi H. Nguyen 2010 University of Texas Graduate School of Biomedical Sciences at Houston

The Expression And Cellular Localization Of Cc-Chemokine Receptor 5 (Ccr5) After Traumatic Brain Injury, Vuvi H. Nguyen

UT GSBS Dissertations and Theses (Open Access)

Traumatic brain injury results from a primary insult and secondary events that together result in tissue injury. This primary injury occurs at the moment of impact and damage can include scalp laceration, skull fraction, cerebral contusions and lacerations as well as intracranial hemorrhage. Following the initial insult, a delayed response occurs and is characterized by hypoxia, ischemia, cerebral edema, and infection. During secondary brain injury, a series of neuroinflammatory events are triggered that can produce additional damage but may also help to protect nervous tissue from invading pathogens and help to repair the damaged tissue. Brain microglia and astrocytes become ...


Developmental Changes In The Structure And Composition Of The Postsynaptic Density, Matthew T. Swulius 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Developmental Changes In The Structure And Composition Of The Postsynaptic Density, Matthew T. Swulius

UT GSBS Dissertations and Theses (Open Access)

The development of the brain and its underlying circuitry is dependent on the formation of trillions of chemical synapses, which are highly specialized contacts that regulate the flow of information from one neuron to the next. It is through these synaptic connections that neurons wire together into networks capable of performing specific tasks, and activity-dependent changes in their structural and physiological state is one way that the brain is thought to adapt and store information. At the ultrastructural level, developmental and activity-dependent changes in the size and shape of dendritic spines have been well documented, and it is widely believed ...


Signaling Mechanisms That Control Gap Junctional Coupling Between Retinal Neurons, Wade Kothmann 2010 University of Texas Graduate School of Biomedical Sciences at Houston

Signaling Mechanisms That Control Gap Junctional Coupling Between Retinal Neurons, Wade Kothmann

UT GSBS Dissertations and Theses (Open Access)

Gap junctions between neurons form the structural substrate for electrical synapses. Connexin 36 (Cx36, and its non-mammalian ortholog connexin 35) is the major neuronal gap junction protein in the central nervous system (CNS), and contributes to several important neuronal functions including neuronal synchronization, signal averaging, network oscillations, and motor learning. Connexin 36 is strongly expressed in the retina, where it is an obligatory component of the high-sensitivity rod photoreceptor pathway. A fundamental requirement of the retina is to adapt to broadly varying inputs in order to maintain a dynamic range of signaling output. Modulation of the strength of electrical coupling ...


Genes Involved In Mushroom Body Development And Behavior In Drosophila, Christine Nicole Serway 2010 University of Nevada Las Vegas

Genes Involved In Mushroom Body Development And Behavior In Drosophila, Christine Nicole Serway

UNLV Theses, Dissertations, Professional Papers, and Capstones

Mushroom bodies (MBs) are the site of multi modal sensory integration critical for associative conditioning in Drosophila. They have been central to research on the structure function relationship in the brain for over one hundred years due to their unique shape and readily accessible physiology. This dissertation incorporates three different approaches to further elucidate the genetic and molecular nature of this structure function relationship.

First, the suite of genetic and molecular tools available in Drosophila melanogaster, facilitated the molecular mapping of a 25-year old MB structural mutant called mushroom body miniature B (mbmB) to the gene Pendulin [Pen, also known ...


Effect Of Membrane Cholesterol Levels And Allelic Variation On Prion Conversion, Ross Hartman 2010 Carroll College, Helena, MT

Effect Of Membrane Cholesterol Levels And Allelic Variation On Prion Conversion, Ross Hartman

Life and Environmental Sciences Undergraduate Theses

Chronic Wasting Disease (CWD) is caused by an accumulation of misfolded prion proteins (PrPsc) and subsequent plaque formation in the central nervous system. CWD is horizontally transferable; misfolded prions from one animal can enter another and cause normal prion proteins (PrPc) to misfold. This misfolding process is termed prion conversion. In natural deer populations an allelic variation in the prion gene is thought to confer resistance to CWD. Wild type mule deer are serine (S) homozygotes at codon 225. Mule deer that are Serine/ Phenyalanine (S/F) heterozygotes exhibit resistance to prion infection. In this study the F encoding allele ...


Dynamics Of The Rapsyn Scaffolding Protein At The Neuromuscular Junction Of Live Mice, Emile Bruneau, Mohammed Akaaboune 2010 University of Pennsylvania

Dynamics Of The Rapsyn Scaffolding Protein At The Neuromuscular Junction Of Live Mice, Emile Bruneau, Mohammed Akaaboune

Departmental Papers (ASC)

The efficacy of synaptic transmission depends on the maintenance of a high density of neurotransmitter receptors and their associated scaffold proteins in the postsynaptic membrane. While the dynamics of receptors has been extensively studied, the dynamics of the intracellular scaffold proteins that make up the postsynaptic density are largely unknown in vivo. Here, we focused on the dynamics of rapsyn, a protein required for the clustering and maintenance of acetylcholine receptor (AChR) density at postsynaptic sites. Using time-lapse imaging, we demonstrated that rapsyn is remarkably dynamic compared to AChRs at functional synapses, turning over 4–6 times more rapidly than ...


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