Medicine and Health Sciences Commons^™

Running Enhances Spatial Pattern Separation In Mice., David J Creer, Carola Romberg, Lisa M Saksida, Henriette Van Praag, Timothy J Bussey

Brain and Mind Institute Researchers' Publications

Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of …

Recent Experimental And Clinical Findings In The Skeleton Associated With Loss Of Estrogen Hormone Or Estrogen Receptor Activity, Eric P. Smith, Bonny Specker, Kenneth S Korach

Ethel Austin Martin Program Publications

Studies on rodent models and rare human disorders of estrogen production or response have revealed an increased complexity of the actions of estrogen on bone. ERalpha disruption in human males results in delayed epiphyseal maturation, tall stature, trabecular thinning, marked cortical thinning, genu valgum and significantly reduced cortical vBMD, but trabecular number is preserved and there is normal to increased periosteal expansion. Aromatase deficiency results overall in a similar phenotype, although less is known about skeletal architecture. Importantly, estrogen replacement in these individuals, even if provided late in the third decade, may normalize aBMD. Less certain is whether there is …

Anti-Argonaute Rip-Chip Shows That Mirna Transfections Alter Global Patterns Of Mrna Recruitment To Microribonucleoprotein Complexes, Wang-Xia Wang, Bernard R. Wilfred, Yanling Hu, Arnold J. Stromberg, Peter T. Nelson

Pathology and Laboratory Medicine Faculty Publications

MicroRNAs (miRNAs) play key roles in gene expression regulation by guiding Argonaute (AGO)-containing microribonucleoprotein (miRNP) effector complexes to target polynucleotides. There are still uncertainties about how miRNAs interact with mRNAs. Here we employed a biochemical approach to isolate AGO-containing miRNPs from human H4 tumor cells by co-immunoprecipitation (co-IP) with a previously described anti-AGO antibody. Co-immunoprecipitated (co-IPed) RNAs were subjected to downstream Affymetrix Human Gene 1.0 ST microarray analysis. During rigorous validation, the "RIP-Chip" assay identified target mRNAs specifically associated with AGO complexes. RIP-Chip was performed after transfecting brain-enriched miRNAs (miR-107, miR-124, miR-128, and miR-320) and nonphysiologic control miRNA to identify …

What Is Biomedical Informatics?, Elmer V Bernstam, Jack W Smith, Todd R Johnson

Faculty, Staff and Student Publications

Biomedical informatics lacks a clear and theoretically-grounded definition. Many proposed definitions focus on data, information, and knowledge, but do not provide an adequate definition of these terms. Leveraging insights from the philosophy of information, we define informatics as the science of information, where information is data plus meaning. Biomedical informatics is the science of information as applied to or studied in the context of biomedicine. Defining the object of study of informatics as data plus meaning clearly distinguishes the field from related fields, such as computer science, statistics and biomedicine, which have different objects of study. The emphasis on data …

Elevated Albumin In Retinas Of Monkeys With Experimental Glaucoma, Louvenia Carter-Dawson, Yujin Zhang, Ronald S Harwerth, Ricky Rojas, Pramod Dash, Xinping C Zhao, Elizabeth Woldemussie, Guadalupe Ruiz, Alice Chuang, William P Dubinsky, John B Redell

Faculty, Staff and Student Publications

PURPOSE: To establish the identity of a prominent protein, approximately 70 kDa, that is markedly increased in the retina of monkeys with experimental glaucoma compared with the fellow control retina, the relationship to glaucoma severity, and its localization in the retina.

METHODS: Retinal extracts were subjected to 2-D gel electrophoresis to identify differentially expressed proteins. Purified peptides from the abundant 70 kDa protein were analyzed and identified by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) separation, and collision-induced dissociation sequencing. Protein identity was performed on MASCOT (Matrix Science, Boston, MA) and confirmed by Western blot. The relationship between the increase in this …

Cardiomyocyte Pdgfr-Beta Signaling Is An Essential Component Of The Mouse Cardiac Response To Load-Induced Stress, Vishnu Chintalgattu, Di Ai, Robert R Langley, Jianhu Zhang, James A Bankson, Tiffany L Shih, Anilkumar K Reddy, Kevin R Coombes, Iyad N Daher, Shibani Pati, Shalin S Patel, Jennifer S Pocius, George E Taffet, L Maximillian Buja, Mark L Entman, Aarif Y Khakoo

Faculty, Staff and Student Publications

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted …

Progressive Changes In Microglia And Macrophages In Spinal Cord And Peripheral Nerve In The Transgenic Rat Model Of Amyotrophic Lateral Sclerosis, David J. Graber, William F. Hickey, Brent T. Harris

Dartmouth Scholarship

The role of neuroinflammation in motor neuron death of amyotrophic lateral sclerosis (ALS) is unclear. The human mutant superoxide dismutase-1 (hmSOD1)-expressing murine transgenic model of ALS has provided some insight into changes in microglia activity during disease progression. The purpose of this study was to gain further knowledge by characterizing the immunological changes during disease progression in the spinal cord and peripheral nerve using the more recently developed hmSOD1 rat transgenic model of ALS. Using immunohistochemistry, the extent and intensity of tissue CD11b expression in spinal cord, lumbar nerve roots, and sciatic nerve were evaluated in hmSOD1 rats that were …

Proliferation Of Aneuploid Human Cells Is Limited By A P53-Dependent Mechanism, Sarah L. Thompson, Duane A. Compton

Dartmouth Scholarship

Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation …

Cd4+ T Cell Regulation Of Cd25 Expression Controls Development Of Short-Lived Effector Cd8+ T Cells In Primary And Secondary Responses, Joshua J. Obar, Michael J. Molloy, Evan R. Jellison, Thomas A. Stoklasek, Weijun Zhang, Edward J. Usherwood, Leo Lefrançois

Dartmouth Scholarship

Both CD4(+) T cell help and IL-2 have been postulated to "program" activated CD8(+) T cells for memory cell development. However, the linkage between these two signals has not been well elucidated. Here we have studied effector and memory CD8(+) T cell differentiation following infection with three pathogens (Listeria monocytogenes, vesicular stomatitis virus, and vaccinia virus) in the absence of both CD4(+) T cells and IL-2 signaling. We found that expression of CD25 on antigen-specific CD8(+) T cells peaked 3-4 days after initial priming and was dependent on CD4(+) T cell help, likely through a CD28:CD80/86 mediated pathway. CD4(+) T …

The Public Health Impacts Of Concentrated Animal Feeding Operations On Local Communities, Michael Greger, Gowri Koneswaran

Environment Collection

Large-scale farm animal production facilities, also known as concentrated animal feeding operations (CAFOs), release a significant amount of contaminants into the air and water. Adverse health effects related to exposure to these contaminants among CAFO workers have been welldocumented; however, less is known about their impact on the health of residents in nearby communities. Epidemiological research in this area suggests that neighboring residents are at increased risk of developing neurobehavioral symptoms and respiratory illnesses, including asthma. Additional research is needed to better understand community-scale exposures and health outcomes related to the management practices and emissions of CAFOs.

Recent Diarrhea Is Associated With Elevated Salivary Igg Responses To Cryptosporidium In Residents Of An Eastern Massachusetts Community, A. I. Egorov, L. M. Montuori Trimble, L. Ascolillo, H. D. Ward, Deborah A. Levy, R. D. Morris, E. N. Naumova, J. K. Griffiths

Journal Articles: Epidemiology

BACKGROUND: Serological data suggest that Cryptosporidium infections are common but underreported. The invasiveness of blood sampling limits the application of serology in epidemiological surveillance. We pilot-tested a non-invasive salivary anti-Cryptosporidium antibody assay in a community survey involving children and adults.

MATERIALS AND METHODS: Families with children were recruited in a Massachusetts community in July; symptoms data were collected at 3 monthly follow-up mail surveys. One saliva sample per person (n = 349) was collected via mail, with the last survey in October. Samples were analyzed for IgG and IgA responses to a recombinant C. hominis gp15 sporozoite protein using a …

Differential Impact Of Tumor Suppressor Pathways On Dna Damage Response And Therapy-Induced Transformation In A Mouse Primary Cell Model., A Kathleen Mcclendon, Jeffry L Dean, Adam Ertel, Erik S Knudsen

Department of Cancer Biology Faculty Papers

The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying …

The Relationship Between Mosquito Abundance And Rice Field Density In The Republic Of Korea, Erin E. Richards, Penny Masuoka, David Brett-Major, Matthew Smith, Terry A. Klein, Heung Chul Kim, Assaf Anyamba, John Grieco

Journal Articles: Epidemiology

BACKGROUND: Japanese encephalitis virus (JEV), the causative agent of Japanese encephalitis (JE), is endemic to the Republic of Korea (ROK) where unvaccinated United States (U.S.) military Service members, civilians and family members are stationed. The primary vector of the JEV in the ROK is Culex tritaeniorhynchus. The ecological relationship between Culex spp. and rice fields has been studied extensively; rice fields have been shown to increase the prevalence of Cx. tritaeniorhynchus. This research was conducted to determine if the quantification of rice field land cover surrounding U.S. military installations in the ROK should be used as a parameter in a …

Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets With Alopecia Resulting From A Novel Missense Mutation In The Dna-Binding Domain Of The Vitamin D Receptor., Peter J. Malloy, Jining Wang, Tarak Srivastava, David Feldman

Manuscripts, Articles, Book Chapters and Other Papers

The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3) or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone X-rays normalized …

Interaction Of The Mu-Opioid Receptor With Gpr177 (Wntless) Inhibits Wnt Secretion: Potential Implications For Opioid Dependence., Jay Jin, Saranya Kittanakom, Victoria Wong, Beverly A S Reyes, Elisabeth J Van Bockstaele, Igor Stagljar, Wade Berrettini, Robert Levenson

Department of Neurosurgery Faculty Papers

BACKGROUND: Opioid agonist drugs produce analgesia. However, long-term exposure to opioid agonists may lead to opioid dependence. The analgesic and addictive properties of opioid agonist drugs are mediated primarily via the mu-opioid receptor (MOR). Opioid agonists appear to alter neuronal morphology in key brain regions implicated in the development of opioid dependence. However, the precise role of the MOR in the development of these neuronal alterations remains elusive. We hypothesize that identifying and characterizing novel MOR interacting proteins (MORIPs) may help to elucidate the underlying mechanisms involved in the development of opioid dependence. RESULTS: GPR177, the mammalian ortholog of Drosophila …

Recent Advances On Skin-Resident Stem/Progenitor Cell Functions In Skin Regeneration, Aging And Cancers And Novel Anti-Aging And Cancer Therapies., Murielle Mimeault, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Recent advances in skin-resident adult stem/progenitor cell research have revealed that these immature and regenerative cells with a high longevity provide critical functions in maintaining skin homeostasis and repair after severe injuries along the lifespan of individuals. The establishment of the functional properties of distinct adult stem/progenitor cells found in skin epidermis and hair follicles and extrinsic signals from their niches, which are deregulated during their aging and malignant transformation, has significantly improved our understanding on the etiopathogenesis of diverse human skin disorders and cancers. Particularly, enhanced ultraviolet radiation exposure, inflammation and oxidative stress and telomere attrition during chronological aging …

Sustained Expression Of Tdp-43 And Fus In Motor Neurons In Rodent's Lifetime., Cao Huang, Pedro Yuxing Xia, Hongxia Zhou

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS) are two highly conserved ribonucleoproteins. Pathogenic mutations of the TDP-43 or the FUS gene are all linked to amyotrophic lateral sclerosis (ALS) that is characterized by progressive degeneration of motor neurons. To better understand the correlation of ALS disease genes with the selectivity of chronic motor neuron degeneration, we examined the longitudinal expression of the TDP-43 and the FUS genes in C57BL6 mice and in Sprague-Dawley rats. TDP-43 and FUS were robustly and ubiquitously expressed in the postnatal mice and rats, but were markedly decreased in the adult rodents. In adulthood, …

More Than Synaptic Plasticity: Role Of Nonsynaptic Plasticity In Learning And Memory, Riccardo Mozzachiodi, John H Byrne

Faculty, Staff and Student Publications

Decades of research on the cellular mechanisms of memory have led to the widely held view that memories are stored as modifications of synaptic strength. These changes involve presynaptic processes, such as direct modulation of the release machinery, or postsynaptic processes, such as modulation of receptor properties. Parallel studies have revealed that memories might also be stored by nonsynaptic processes, such as modulation of voltage-dependent membrane conductances, which are expressed as changes in neuronal excitability. Although in some cases nonsynaptic changes can function as part of the engram itself, they might also serve as mechanisms through which a neural circuit …

Imaging Spontaneous Mmtvneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products., Mathew L Thakur, Devakumar Devadhas, Kaijun Zhang, Richard G Pestell, Chenguang Wang, Peter Mccue, Eric Wickstrom

Department of Radiology Faculty Papers

INTRODUCTION: Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for …

Anomalous Constitutive Src Kinase Activity Promotes B Lymphoma Survival And Growth, Jiyuan Ke, R. Lakshman Chelvarajan, Vishal Sindhava, Darrell A. Robertson, Lazaros Lekakis, C. Darrell Jennings, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background: Previously we have shown that B cell receptor (BCR) expression and B cell receptor signaling pathways are important for the basal growth of B lymphoma cells. In particular we have shown that the activation of Syk, a non-src family protein tyrosine kinase and the mitogen activated protein kinases (MAPK), ERK and JNK that mediate BCR signals are required for the constitutive growth of B lymphoma cells. Since src family protein tyrosine kinases (SFKs) like Lyn are known to be needed for the phosphorylation of BCR co-receptors, Ig-alpha and Ig-beta, we hypothesized that one or more SFKs will be constitutively …

Transcriptional Adaptations Following Exercise In Thoroughbred Horse Skeletal Muscle Highlights Molecular Mechanisms That Lead To Muscle Hypertrophy, Beatrice A. Mcgivney, Suzanne S. Eivers, David E. Machugh, James N. Macleod, Grace M. O'Gorman, Stephen D.E. Park, Lisa M. Katz, Emmeline W. Hill

Veterinary Science Faculty Publications

BACKGROUND: Selection for exercise-adapted phenotypes in the Thoroughbred racehorse has provided a valuable model system to understand molecular responses to exercise in skeletal muscle. Exercise stimulates immediate early molecular responses as well as delayed responses during recovery, resulting in a return to homeostasis and enabling long term adaptation. Global mRNA expression during the immediate-response period has not previously been reported in skeletal muscle following exercise in any species. Also, global gene expression changes in equine skeletal muscle following exercise have not been reported. Therefore, to identify novel genes and key regulatory pathways responsible for exercise adaptation we have used equine-specific …

Chylomicrons Promote Intestinal Absorption And Systemic Dissemination Of Dietary Antigen (Ovalbumin) In Mice, Yuehui Wang, Sarbani Ghoshal, Martin Ward, Willem De Villiers, Jerold Woodward, Erik Eckhardt

Internal Medicine Faculty Publications

BACKGROUND: A small fraction of dietary protein survives enzymatic degradation and is absorbed in potentially antigenic form. This can trigger inflammatory responses in patients with celiac disease or food allergies, but typically induces systemic immunological tolerance (oral tolerance). At present it is not clear how dietary antigens are absorbed. Most food staples, including those with common antigens such as peanuts, eggs, and milk, contain long-chain triglycerides (LCT), which stimulate mesenteric lymph flux and postprandial transport of chylomicrons through mesenteric lymph nodes (MLN) and blood. Most dietary antigens, like ovalbumin (OVA), are emulsifiers, predicting affinity for chylomicrons. We hypothesized that chylomicron …

Gbdr Regulates Pseudomonas Aeruginosa Plch And Pchp Transcription In Response To Choline Catabolites, Matthew J. Wargo, Tiffany C. Ho, Maegan J. Gross, Laurie A. Whittaker, Deborah A. Hogan

Dartmouth Scholarship

Pseudomonas aeruginosa hemolytic phospholipase C, PlcH, can degrade phosphatidylcholine (PC) and sphingomyelin in eukaryotic cell membranes and extracellular PC in lung surfactant. Numerous studies implicate PlcH in P. aeruginosa virulence. The phosphorylcholine released by PlcH activity on phospholipids is hydrolyzed by a periplasmic phosphorylcholine phosphatase, PchP. Both plcH gene expression and PchP enzyme activity are positively regulated by phosphorylcholine degradation products, including glycine betaine. Here we report that the induction of plcH and pchP transcription by glycine betaine is mediated by GbdR, an AraC family transcription factor. Mutants that lack gbdR are unable to induce plcH and pchP in media …

Germinal Center Reutilization By Newly Activated B Cells., Tanja A Schwickert, Boris Alabyev, Tim Manser, Michel C Nussenzweig

Department of Microbiology and Immunology Faculty Papers

Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude …

Regulation Of Cellular Protein Phosphatase-1 (Pp1) By Phosphorylation Of The Cpi-17 Family, C-Kinase-Activated Pp1 Inhibitors., Masumi Eto

Department of Molecular Physiology and Biophysics Faculty Papers

The regulatory circuit controlling cellular protein phosphatase-1 (PP1), an abundant group of Ser/Thr phosphatases, involves phosphorylation of PP1-specific inhibitor proteins. Malfunctions of these inhibitor proteins have been linked to a variety of diseases, including cardiovascular disease and cancer. Upon phosphorylation at Thr(38), the 17-kDa PP1 inhibitor protein, CPI-17, selectively inhibits a specific form of PP1, myosin light chain phosphatase, which transduces multiple kinase signals into the phosphorylation of myosin II and other proteins. Here, the mechanisms underlying PP1 inhibition and the kinase/PP1 cross-talk mediated by CPI-17 and its related proteins, PHI, KEPI, and GBPI, are discussed.

Oocyte Peptides As Paracrine Tools For Ovarian Stimulation And Oocyte Maturation., David G Mottershead, Andrew J Watson

Obstetrics & Gynaecology Publications

Recent studies report the production and isolation of a stable bioactive recombinant human bone morphogenetic protein 15 (rhBMP15) that is appropriately processed in HEK-293 cells and activates the SMAD 1/5/8 pathway in mouse granulosa cell cultures. Further, the purified rhBMP15 induces the expression of genes associated with cumulus expansion. Thanks to recent research, we have a greater understanding of the importance of the dialogue that occurs between the oocyte and the granulosa cell layer with regard to regulating folliculogenesis and the acquisition of oocyte developmental competence and maturation. BMP15 is one of the critical components of these intra-follicular communication pathways. …

Manganese Flux Across The Blood-Brain Barrier, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is essential for brain growth and metabolism, but in excess can be a neurotoxicant. The chemical form (species) of Mn influences its kinetics and toxicity. Significant Mn species entering the brain are the Mn²⁺ ion and Mn citrate which, along with Mn transferrin, enter the brain by carrier-mediated processes. Although the divalent metal transporter (DMT-1) was suggested to be a candidate for brain Mn uptake, brain Mn influx was not different in Belgrade rats, which do not express functional DMT-1, compared to controls. Brain Mn influx was not sodium dependent or dependent on ATP hydrolysis, but was …

Il-4(-/-) Mice With Lethal Mesocestoides Corti Infections--Reduced Th2 Cytokines And Alternatively Activated Macrophages., A. E. O'Connell, L. A. Kerepesi, G. L. Vandergrift, D. R. Herbert, T J. Van Winkle, D. C. Hooper, E J. Pearce, D. Abraham

Department of Microbiology and Immunology Faculty Papers

Protection against Mesocestoides corti, a cestode that invades vital organs, is dependent on the production of IL-4, as IL-4(-/-) mice were found to have higher parasite burdens when compared with wild-type mice. The goal of this study was to investigate the role of IL-4 in immunity to M. corti, focusing on the immunological profile and on potential mediators of pathology. IL-4(-/-) mice infected with M. corti showed 100% mortality by 32 days, whereas wild-type mice survived for approximately 1 year. Parasite burdens were significantly increased in the liver, peritoneal, and thoracic cavities of IL-4(-/-) mice, associated with impaired recruitment of …

Mepe/Of45 Protects Cells From Dna Damage Induced Killing Via Stabilizing Chk1., Shuang Liu, Hongyan Wang, Xiang Wang, Lin Lu, Ning Gao, Peter S N Rowe, Baocheng Hu, Ya Wang

Department of Radiation Oncology Faculty Papers

Matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) was cloned in 2000 with functions related to bone metabolism. We identified MEPE/OF45 for the first time as a new co-factor of CHK1 in mammalian cells to protect cells from DNA damage induced killing. We demonstrate here that MEPE/OF45 directly interacts with CHK1. Knocking down MEPE/OF45 decreases CHK1 levels and sensitizes the cells to DNA damage inducers such as ionizing radiation (IR) or camptothicin (CPT)-induced killing. Over-expressing wild-type MEPE/OF45, but not the mutant MEPE/OF45 (depleted the key domain to interact with CHK1) increases CHK1 levels in the cells and increases the resistance of the …

Mitochondrial Mislocalization Underlies Abeta42-Induced Neuronal Dysfunction In A Drosophila Model Of Alzheimer's Disease., Kanae Iijima-Ando, Stephen A Hearn, Christopher Shenton, Anthony Gatt, Lijuan Zhao, Koichi Iijima

Department of Biochemistry and Molecular Biology Faculty Papers

The amyloid-beta 42 (Abeta42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial …