Nervous System Diseases Commons^™

Association Of Ubqln1 Mutation With Brown-Vialetto-Van Laere Syndrome But Not Typical Als, Paloma Gonzalez-Perez, Yubing Lu, Ru-Ju Chian, Peter Sapp, Rudolph Tanzi, Lars Bertram, Diane Mckenna-Yasek, Fen-Biao Gao, Robert Brown

Dr Robert Brown

Genetic variants in UBQLN1 gene have been linked to neurodegeneration and mutations in UBQLN2 have recently been identified as a rare cause of amyotrophic lateral sclerosis (ALS). OBJECTIVE: To test if genetic variants in UBQLN1 are involved in ALS. METHODS: 102 and 94 unrelated patients with familial and sporadic forms of ALS were screened for UBQLN1 gene mutations. Single nucleotide variants were further screened in a larger set of sporadic ALS (SALS) patients and unrelated control subjects using high-throughput Taqman genotyping; variants were further assessed for novelty using the 1000Genomes and NHLBI databases. In vitro studies tested the effect of …

Genetic Determinants Of Cerebral Edema In Severe Traumatic Brain Injury: A Pilot Study Of The Role Of Cacna1 And Aqp4 Gene Mutations, Raphael A. Carandang, Susanne Muehlschlegel, Wiley R. Hall, Cynthia Ouillette, Robert H. Brown Jr.

Dr Robert Brown

Cerebral edema is the one of the most significant predictors of poor outcome after traumatic brain injury. It is still unclear what the pathophysiological and cellular mechanisms and predictors of post-traumatic edema are. The exponential growth in genetic information has opened an avenue for investigation in traumatic brain injury and implicated specific genes in the pathophysiology of post-traumatic injury edema. Two examples are the Aquaporin-4 and CACNA1 genes, which respectively encode water and calcium channels. The Aquaporin-4 gene on chromosome 18q11.2-12.1 encodes the Aquaporin-4 protein (AQP4) water channel. AQP4 is one of the bidirectional high capacity water channels that is …

Pharmacokinetics And Brain Uptake In The Rhesus Monkey Of A Fusion Protein Of Arylsulfatase A And A Monoclonal Antibody Against The Human Insulin Receptor, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, Rachita K. Sumbria, William M. Pardridge

Pharmacy Faculty Articles and Research

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, …

An Investigation Into The Combined Effects Of Β-Amyloid Toxicity And Cerebral Ischemia On The Pathological Expression Of Gangliosides., Jeffrey D. Hepburn

Electronic Thesis and Dissertation Repository

Identifying mechanisms underlying the synergistic pathological interaction between stroke and Alzheimer’s disease (AD) can effectively guide future therapeutic strategies for these highly co-morbid conditions. Aberrant ganglioside expression marked by the pathological accumulation of ganglioside GM3 is common to stroke and AD, yet it is unclear whether GM3 is synergistically enhanced in a comorbid model, or if GM3 is a viable therapeutic target. Adult male Wistar rats received a unilateral ischemic striatal infarct via endothelin-1 (ET-1) injection alone or in combination with bilateral intracerebroventricular injection of the β-Amyloid 25-35 peptide (Aβ) to induce generalized Aβ toxicity (Aβ/ET-1). Animals were sacrificed after …

Novel Use Of Dual Anti-Inflammatory Therapy To Overcome Drug Resistance And Improve Functional Recovery Following Spinal Cord Injury, Jennifer Dulin

Dissertations & Theses (Open Access)

Over 1.2 million Americans are currently living with a traumatic spinal cord injury (SCI). Despite the need for effective therapies, there are currently no proven effective treatments that can improve recovery of function in SCI patients. Many therapeutic compounds have shown promise in preclinical models of SCI, but all of these have fallen short in clinical trials.

P-glycoprotein (Pgp) is an active transporter expressed on capillary endothelial cell membranes at the blood-spinal cord barrier (BSCB). Pgp limits passive diffusion of blood-borne drugs into the CNS, by actively extruding drugs from the endothelial cell membrane. Pgp can become pathologically up-regulated, thus …

Parkinson’S Disease: Molecular Mechanisms And Treatments, Delia Vahey

Senior Honors Theses

Parkinson’s disease is a motor system disorder that is caused primarily by the loss of dopamine-producing brain cells. The most affected brain structure is the pars compacta of the substantia nigra. This area of the brain is essential to the control of voluntary movement, and so its impairment leads to symptoms such as tremors, rigidity, and impaired balance. The neuronal protein alpha-synuclein has been shown to be heavily involved in the pathogenesis of the disease at the cellular level. The currently available treatments for PD mainly target dopamine regulation, and there been no cure developed for the disease at present. …

Microrna-Regulated, Systemically Delivered Raav9: A Step Closer To Cns-Restricted Transgene Expression, Jun Xie, Qing Xie, Hongwei Zhang, Stefan L. Ameres, Jui-Hung Hung, Qin Su, Ran He, Xin Mu, Seemin Seher Ahmed, Soyeon Park, Hiroki Kato, Chengjian Li, Christian Mueller, Craig C. Mello, Zhiping Weng, Terence R. Flotte, Phillip D. Zamore, Guangping Gao

Christian Mueller

Recombinant adeno-associated viruses (rAAVs) that can cross the blood-brain-barrier and achieve efficient and stable transvascular gene transfer to the central nervous system (CNS) hold significant promise for treating CNS disorders. However, following intravascular delivery, these vectors also target liver, heart, skeletal muscle, and other tissues, which may cause untoward effects. To circumvent this, we used tissue-specific, endogenous microRNAs (miRNAs) to repress rAAV expression outside the CNS, by engineering perfectly complementary miRNA-binding sites into the rAAV9 genome. This approach allowed simultaneous multi-tissue regulation and CNS-directed stable transgene expression without detectably perturbing the endogenous miRNA pathway. Regulation of rAAV expression by miRNA …

Ginkgo Extract Egb761 Confers Neuroprotection By Reduction Of Glutamate Release In Ischemic Brain, Alexander Mdzinarishvili, Rachita K. Sumbria, Dorothee Lang, Jochen Klein

Pharmacy Faculty Articles and Research

Purpose - Ginkgo extract EGb761 has shown anti-edema and anti-ischemic effects in various experimental models. In the present study, we demonstrate neuroprotective effects of EGb761 in experimental stroke while monitoring brain metabolism by microdialysis. Methods - We have used oxygen-glucose deprivation in brain slices in vitro and middle cerebral artery occlusion (MCAO) in vivo to induce ischemia in mouse brain. We used microdialysis in mouse striatum to monitor extracellular concentrations of glucose and glutamate. Results - In vitro, EGb761 reduced ischemia-induced cell swelling in hippocampal slices by 60%. In vivo, administration of EGb761 (300 mg/kg) reduced cell degeneration and edema …

Notch Regulation Of Adam12 Expression In Glioblastoma Multiforme, Ala'a S. Alsyaideh

Masters Theses 1911 - February 2014

Glioblastoma is the most common malignant brain tumor, accounting for 17% of all primary brain tumors in the United States. Despite the available surgical, radiation, and chemical therapeutic options, the invasive and infiltrative nature of the tumor render current treatment options minimally effective. Recent reports have identified multiple regulators of glioblastoma progression and invasiveness. It has been demonstrated that ADAM12, A Disintegrin And Metalloproteinase encoded by ADAM12 gene, is over-expressed in glioblastoma and directly correlated with tumor proliferation. Additionally, dysregulation of the Notch signaling pathway has been implicated in the pathogenesis of many gliomas. Lastly, an evolving role of microRNAs, …

The Effect Of Load On Movement Coordination During Sled Towing, Michael Lawrence, Daniel Leib, Cara Masterson, Erin Hartigan

Daniel Leib

INTRODUCTION Towing sleds while walking is a popular resistance exercise for the healthy athlete. One reason for the popularity of sled towing is that it is widely believed to be a ‘functional’ exercise. Preliminary research suggests towing while walking can increases lower extremity moment impulses; however whether towing a sled utilizes the same coordination patterns as un-resisted walking is unknown. While altered patterns may not be as relevant to a healthy athlete, sled towing is also sometimes used in the rehabilitation of athletes who sustained a lower extremity injury (anterior cruciate ligament rupture) with the goal of regaining movement symmetry. …

Effects Of Fatigue On Golf Performance, Daniel J. Leib, Nicholas R. Higdon, W. Holmes Finch, Eric L. Dugan

Daniel Leib

No abstract provided.

The Cellular Nucleic Acid Binding Protein Regulates The Alzheimer’S Disease Β-Secretase Protein Bace1, Christopher J. Holler

Theses and Dissertations--Molecular and Cellular Biochemistry

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly population and is believed to be caused by the overproduction and accumulation of the toxic amyloid beta (Aβ) peptide in the brain. Aβ is produced by two separate enzymatic cleavage events of the larger membrane bound amyloid precursor protein, APP. The first, and rate-limiting, cleavage event is made by beta-secretase, or BACE1, and is thus an attractive therapeutic target. Our lab, as well as many others, has shown that BACE1 protein and activity are increased in late-stage sporadic AD. We have extended these findings to show that BACE1 …

Role Of The Gcn5 Histone Acetyltransferase In Spinocerebellar Ataxia Type 7 And In Immature Neurons, Yi Chun Chen

Dissertations & Theses (Open Access)

Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease caused by expansion of a CAG repeat encoding a polyglutamine tract in ATXN7, a component of the SAGA histone acetyltransferase (HAT) complex. Previous studies provided conflicting evidence regarding the effects of polyQ-ATXN7 on the activity of Gcn5, the HAT catalytic subunit of SAGA. Here I showed that reducing Gcn5 expression accelerates both cerebellar and retinal degeneration in a mouse model of SCA7. Deletion of Gcn5 in Purkinje cells in mice expressing wild type Atxn7, however, causes only mild ataxia and does not lead to the early lethality observed in SCA7 mice. …

Exploring The Role Of The Solvent In The Denaturation Of A Protein: A Molecular Dynamics Study Of The Dna Binding Domain Of The 434 Repressor, Celia Schiffer, Volker Dötsch, Kurt Wuthrich, Wilfred Van Gunsteren

Celia A. Schiffer

Molecular dynamics simulations of the DNA binding domain of 434 repressor are presented which aim at unraveling the role of solvent in protein denaturation. Four altered solvent models, each mimicking various possible aspects of the addition of a denaturant to the aqueous solvent, were used in the simulations to analyze their effects on the stability of the protein. The solvent was altered by selectively changing the Coulombic interaction between water and protein atoms and between different water molecules. The use of a modified solvent model has the advantage of mimicking the presence of denaturant without having denaturant molecules present in …

Neuroprotective Effects Of Bilobalide Are Accompanied By A Reduction Of Ischemia-Induced Glutamate Release In Vivo, Dorothee Lang, Cornelia Kiewert, Alexander Mdzinarishvili, Tina Maria Schwarzkopf, Rachita K. Sumbria, Joachim Hartmann, Jochen Klein

Pharmacy Faculty Articles and Research

Neuroprotective properties of bilobalide, a specific constituent of Ginkgo extracts, were tested in a mouse model of stroke. After 24 h of middle cerebral artery occlusion (MCAO), bilobalide reduced infarct areas in the core region (striatum) by 40–50% when given at 10 mg/kg 1 h prior to MCAO. Neuroprotection was also observed at lower doses, or when the drug was given 1 h past stroke induction. Sensorimotor function in mice was improved by bilobalide as shown by corner and chimney tests. When brain metabolism in situ was monitored by microdialysis, MCAO caused a rapid disappearance of extracellular glucose in the …

Upregulation Of Reactive Oxygen Species During The Retrovirus Life Cycle And Their Roles In A Mutant Of Moloney Murine Leukemia Virus, Ts1-Mediated Neurodegeneration, Soo Jin Kim

Dissertations & Theses (Open Access)

Viral invasion of the central nervous system (CNS) and development of neurological symptoms is a characteristic of many retroviruses. The mechanism by which retrovirus infection causes neurological dysfunction has yet to be fully elucidated. Given the complexity of the retrovirus-mediated neuropathogenesis, studies using small animal models are extremely valuable. Our laboratory has used a mutant moloney murine leukemia retrovirus, ts1-mediated neurodegneration. We hypothesize that astrocytes play an important role in ts1-induced neurodegeneration since they are retroviral reservoirs and supporting cells for neurons. It has been shown that ts1 is able to infect astrocytes in vivo and in …

Unifying The Mathematical Modeling Of In Vivo And In Vitro Microdialysis, Peter M. Bungay, Rachita K. Sumbria, Ulrich Bickel

Pharmacy Faculty Articles and Research

A unifying approach is presented for developing mathematical models of microdialysis that are applicable to both in vitro and in vivo situations. Previous models for cylindrical probes have been limited by accommodating analyte diffusion through the surrounding medium in the radial direction only, i.e., perpendicular to the probe axis, or by incomplete incorporation of diffusion in the axial direction. Both radial and axial diffusion are included in the present work by employing two-dimensional finite element analysis. As in previous models, the nondimensional clearance modulus (Θ) represents the degree to which analyte clearance from the external medium influences diffusion through the …

A Time-Efficient Method For Analyzing Bone Strain With Large Subject Pools, Daniel Leib, Eric Dugan, Henry Wang

Daniel Leib

No abstract provided.

Eye Movement Measures Of Cognitive Control In Children With Tourette Syndrome, Cameron B. Jeter

Dissertations & Theses (Open Access)

Tourette Syndrome begins in childhood and is characterized by uncontrollable repetitive actions like neck craning or hopping and noises such as sniffing or chirping. Worst in early adolescence, these tics wax and wane in severity and occur in bouts unpredictably, often drawing unwanted attention from bystanders. Making matters worse, over half of children with Tourette Syndrome also suffer from comorbid, or concurrent, disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). These disorders introduce anxious thoughts, impulsivity, inattention, and mood variability that further disrupt children with Tourette Syndrome from focusing and performing well at school and home. …

An Epitope From Acanthamoeba Castellanii That Cross-React With Proteolipid Protein 139-151-Reactive T Cells Induces Autoimmune Encephalomyelitis In Sjl Mice, Chandirasegaran Massilamany, David Steffan, Jay Reddy

Jay Reddy Publications

We report here that an epitope (aa, 83-95) derived from Acanthamoeba castellanii (ACA) induces clinical signs of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice reminiscent of the disease induced with myelin proteolipid protein (PLP) 139-151. By using IA^s/tetramers, we demonstrate that both ACA 83-95 and PLP 139-151 generate antigen-specific cross-reactive CD4 T cells and the T cells secrete identical patterns of cytokines and induce EAE with a similar severity. These results may provide insights into the pathogenesis of multiple sclerosis and ACA-induced granulomatous encephalitis.

An Integrated Modeling Method For Bone Strain Analysis, Daniel Leib, Henry Wang, Eric Dugan

Daniel Leib

No abstract provided.

An Integrated Modeling Method For Tibia Strain Analysis, Daniel Leib, Henry Wang

Daniel Leib

No abstract provided.

Muscular Fatigue Increases Ground Reaction Loading Rate During Walking, Henry Wang, Jeff Frame, Elicia Ozimek, Cara Reedstrom, Daniel Leib, Eric Dugan

Daniel Leib

No abstract provided.

Genetic Connections Between Neurological Disorders And Cholesterol Metabolism, Ingemar Bjorkhem, Valerio Leoni, Steve Meaney

Articles

Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally …

Validation Of A Serotonin Depletion Checklist In Parkinson’S Disease, Kelly Diane Darby Holder

Loma Linda University Electronic Theses, Dissertations & Projects

The distinctive pathological marker of Parkinson’s Disease (PD) is the progressive death of neurons that produce dopamine; however, there are also major alterations in the production of quantities of other neurotransmitters, such as norepinephrine and serotonin that contribute to the signs, symptoms, neuropsychological manifestations of the diseases. PD patients can be divided into classes based on the manifestation of motor symptoms, type A, classified as tremor dominant, and type B PD, classified as akinetic. Type B PD patients, often manifest symptoms in which serotonin deficiency plays an important role, such as frontal cognitive impairments, which often includes a history of …

Combining Cytotoxic And Immune-Mediated Gene Therapy To Treat Brain Tumors, James Curtin, Gwendalyn King, Marianela Candolfi, Remy Greeno, Kurt Kroeger, Pedro Lowenstein, Maria Castro

Articles

Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all …

Gene Therapy And Targeted Toxins For Glioma, James Curtin, Gwendalyn King, Marianela Candolfi, Kurt Kroeger, Pedro Lowenstein, Maria Castro

Articles

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted …

Regulation Of Proto-Oncogenes Expression In Developmental Epilepsy, Mahnoush Shafiei

Seton Hall University Dissertations and Theses (ETDs)

Seizures cause selective neuronal cell loss in vulnerable regions such as the hippocampus, cortex, thalamus or substantia nigra (SN) in human or experimental animals. While the HF can propagate seizures, the SN pars reticulata (SNR) regulates the spread ol seizures in an age-dependent fashion, and the pars compacta (SNC) affects extrapyramidal motor control. In mature animals, both structures are wlnerable to seizure-induced damage. In prepubescent rats, seizure susceptibility is reduced and CA 1 region rs primarily affected. The proto-oncogenes, Bcl-2 and Bax, encode specific proteins that inhibit and promote programmed cell death, respectively. In order to determine whether proto-oncogenes are …

Neuronal And Metabolic Increases In Pedunculopontine Nucleus Of Parkinson's Rats, Jonathan Dennis Carlson

Loma Linda University Electronic Theses, Dissertations & Projects

The theoretical mechanisms underlying the symptoms of Parkinson’s disease are based on dysfunctional output from the basal ganglia projected to the cortex via the thalamus. However, the subthalamic nucleus (STN) and substantia nigra pars reticularis (SNr) as part of the basal ganglia, also project to the brainstem, in particular to the pedunculopontine nucleus (PPN). Both the STN and SNr have altered neuronal activity in the 6-hydroxydopamine (6-OHDA) Parkinson’s model rat. Thus, it is hypothesized that the PPN is altered in this model of Parkinson’s disease.

This hypothesis was examined by comparing the rates of glucose metabolism and spontaneous neuronal activity …

Increased Glutathione Metabolic Defense Capabilities In Cultured Alzheimer's Diseased Lymphoblast Cell Lines, Collin M. Shaw

Dissertations and Theses

The hypothesis to be tested states that the pathology of Alzheimer's disease (AD) involves elevated levels of oxidative stress, resulting in elevated levels of cellular oxidative defense mechanisms. If the premise is true, than AD pathologically afflicted cells should have a higher demand for glutathione (GSH) as an innate oxidative defense mechanism hence; greater GSH concentrations, increased GSH resynthesis capabilities, and increased levels of cystathionine gamma-lyase (CNase). Alzheimer diseased and age matched control lymphoblast cells, obtained from OHSU's Oregon Brain Aging Study, were cultured, and GSH biochemistry was subsequently evaluated. GSH was depleted by exposing cells to the GSH depleting …