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https://www.readbyqxmd.com/read/29418019/new-developments-in-genetic-rat-models-of-parkinson-s-disease
#1
REVIEW
Rose B Creed, Matthew S Goldberg
Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD...
February 8, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29397558/glutamate-excitotoxicity-linked-to-spermine-oxidase-overexpression
#2
Stefano Pietropaoli, Alessia Leonetti, Chiara Cervetto, Arianna Venturini, Roberta Mastrantonio, Giulia Baroli, Tiziana Persichini, Marco Colasanti, Guido Maura, Manuela Marcoli, Paolo Mariottini, Manuela Cervelli
Excitotoxic stress has been associated with several different neurological disorders, and it is one of the main causes of neuronal degeneration and death. To identify new potential proteins that could represent key factors in excitotoxic stress and to study the relationship between polyamine catabolism and excitotoxic damage, a novel transgenic mouse line overexpressing spermine oxidase enzyme in the neocortex (Dach-SMOX) has been engineered. These transgenic mice are more susceptible to excitotoxic injury and display a higher oxidative stress, highlighted by 8-Oxo-2'-deoxyguanosine increase and activation of defense mechanisms, as demonstrated by the increase of nuclear factor erythroid 2-related factor 2 (Nrf-2) in the nucleus...
February 3, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29378824/chromosomal-instability-during-neurogenesis-in-huntington-s-disease
#3
Albert Ruzo, Gist F Croft, Jakob J Metzger, Szilvia Galgoczi, Lauren J Gerber, Cecilia Pellegrini, Hanbin Wang, Maria Fenner, Stephanie Tse, Adam Marks, Corbyn Nchako, Ali H Brivanlou
Huntington's disease (HD) is a fatal neurodegenerative disease caused by expansion of CAG repeats in the Huntingtin gene (HTT). Neither its pathogenic mechanisms nor the normal functions of HTT are well understood. To model HD in humans, we engineered a genetic allelic series of isogenic human embryonic stem cell (hESC) lines with graded increases in CAG repeat length. Neural differentiation of these lines unveiled a novel developmental HD phenotype: the appearance of giant multinucleated telencephalic neurons at an abundance directly proportional to CAG repeat length, generated by a chromosomal instability and failed cytokinesis over multiple rounds of DNA replication...
January 29, 2018: Development
https://www.readbyqxmd.com/read/29371319/altered-baseline-and-nicotine-mediated-behavioral-and-cholinergic-profiles-in-chat-cre-mouse-lines
#4
Edison Chen, Valeria Lallai, Yasmine Sherafat, Nickolas P Grimes, Anna N Pushkin, J P Fowler, Christie D Fowler
The recent development of transgenic rodent lines expressing cre recombinase in a cell-specific manner, along with advances in engineered viral vectors, has permitted in-depth investigations into circuit function. However, emerging evidence has begun to suggest that genetic modifications may introduce unexpected caveats. In the current studies, we sought to extensively characterize male and female mice from both the ChAT(BAC)-Cre mouse line, created with the bacterial artificial chromosome (BAC) method, and ChAT(IRES)-Cre mouse line, generated with the internal ribosome entry site (IRES) method...
January 25, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29369447/critical-reappraisal-of-mechanistic-links-of-copy-number-variants-to-dimensional-constructs-of-neuropsychiatric-disorders-in-mouse-models
#5
Noboru Hiroi
Copy number variants are deletions and duplications of a few thousand to million base pairs and are associated with extraordinarily high levels of autism spectrum disorder, schizophrenia, intellectual disability or attention-deficit/hyperactivity disorder. The unprecedented levels of robust and reproducible penetrance of copy number variants make them one of the most promising and reliable entry points to delve into the mechanistic bases of many mental disorders. However, the precise mechanistic bases of these associations still remain elusive in humans due to the many genes encoded in each copy number variant and the diverse associated phenotypic features...
January 25, 2018: Psychiatry and Clinical Neurosciences
https://www.readbyqxmd.com/read/29361543/mechano-sensitization-of-mammalian-neuronal-networks-through-expression-of-the-bacterial-mechanosensitive-mscl-channel
#6
Alessandro Soloperto, Anna Boccaccio, Andrea Contestabile, Monica Moroni, Grace I Hallinan, Gemma Palazzolo, John Chad, Katrin Deinhardt, Dario Carugo, Francesco Difato
Development of remote stimulation techniques for neuronal tissues represents a challenging goal. Among the potential methods, mechanical stimuli are the most promising vector to convey information non-invasively into intact brain tissue. In this context, selective mechano-sensitization of neuronal circuits would pave the way to develop a new cell-type specific stimulation approach. We report here for the first time the development and characterization of mechano-sensitized neuronal networks through the heterologous expression of an engineered bacterial large conductance mechanosensitive ion channel (MscL)...
January 19, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29352128/phosphorylation-of-the-transient-receptor-potential-ankyrin-1-by-cyclin-dependent-kinase-5-affects-chemo-nociception
#7
Bradford E Hall, Michaela Prochazkova, Matthew R Sapio, Paul Minetos, Natalya Kurochkina, B K Binukumar, Niranjana D Amin, Anita Terse, John Joseph, Stephen J Raithel, Andrew J Mannes, Harish C Pant, Man-Kyo Chung, Michael J Iadarola, Ashok B Kulkarni
Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase that is upregulated during inflammation, and can subsequently modulate sensitivity to nociceptive stimuli. We conducted an in silico screen for Cdk5 phosphorylation sites within proteins whose expression was enriched in nociceptors and identified the chemo-responsive ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) as a possible Cdk5 substrate. Immunoprecipitated full length TRPA1 was shown to be phosphorylated by Cdk5 and this interaction was blocked by TFP5, an inhibitor that prevents activation of Cdk5...
January 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29318513/targeted-elimination-of-mutant-mitochondrial-dna-in-melas-ipscs-by-mitotalens
#8
Yi Yang, Han Wu, Xiangjin Kang, Yanhui Liang, Ting Lan, Tianjie Li, Tao Tan, Jiangyun Peng, Quanjun Zhang, Geng An, Yali Liu, Qian Yu, Zhenglai Ma, Ying Lian, Boon Seng Soh, Qingfeng Chen, Ping Liu, Yaoyong Chen, Xiaofang Sun, Rong Li, Xiumei Zhen, Ping Liu, Yang Yu, Xiaoping Li, Yong Fan
Mitochondrial diseases are maternally inherited heterogeneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruction of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m...
January 9, 2018: Protein & Cell
https://www.readbyqxmd.com/read/29306662/ciguatoxins-activate-the-calcineurin-signalling-pathway-in-yeasts-potential-for-development-of-an-alternative-detection-tool
#9
Hélène Martin-Yken, Camille Gironde, Sylvain Derick, Hélène Taiana Darius, Christophe Furger, Dominique Laurent, Mireille Chinain
Ciguatoxins (CTXs) are lipid-soluble polyether compounds produced by dinoflagellates from the genus Gambierdiscus spp. typically found in tropical and subtropical zones. This endemic area is however rapidly expanding due to environmental perturbations, and both toxic Gambierdiscus spp. and ciguatoxic fishes have been recently identified in the North Atlantic Ocean (Madeira and Canary islands) and Mediterranean Sea. Ciguatoxins bind to Voltage Gated Sodium Channels on the membranes of sensory neurons, causing Ciguatera Fish Poisoning (CFP) in humans, a disease characterized by a complex array of gastrointestinal, neurological, neuropsychological, and cardiovascular symptoms...
January 4, 2018: Environmental Research
https://www.readbyqxmd.com/read/29305530/role-of-purinergic-receptor-p2y1-in-spatiotemporal-ca2-dynamics-in-astrocytes
#10
Eiji Shigetomi, Yukiho J Hirayama, Kazuhiro Ikenaka, Kenji F Tanaka, Schuichi Koizumi
Fine processes of astrocytes enwrap synapses and are well-positioned to sense neuronal information via synaptic transmission. In rodents, astrocyte processes sense synaptic transmission via Gq-protein coupled receptors (GqPCR), including the P2Y1 receptor (P2Y1R), to generate Ca2+ signals. Astrocytes display numerous spontaneous microdomain Ca2+ signals; however, it is not clear if such signals are due to local synaptic transmission and/or in what timeframe astrocytes sense local synaptic transmission. To ask if GqPCRs mediate microdomain Ca2+ signals, we engineered mice (both sexes) to specifically overexpress P2Y1Rs in astrocytes and we visualized Ca2+ signals via a genetically encoded Ca2+ indicator, GCaMP6f, in astrocytes from adult mice...
January 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29285820/maldi-imaging-detects-endogenous-digoxin-in-glioblastoma-cells-infected-by-zika-virus-would-it-be-the-oncolytic-key
#11
Estela de O Lima, Tatiane M Guerreiro, Carlos Fernando O R Melo, Diogo N de Oliveira, Daisy Machado, Marcelo Lancelloti, Rodrigo R Catharino
Recently, microcephaly cases have increased in Americas and have been matter of concern due to Zika virus (ZIKV) recent outbreak. Previous studies have shown that ZIKV-infected progenitor neuronal cells present morphological abnormalities and increased rates of cell death, which may be indicators of microcephaly causes. As recent studies indicate Zika virus' tropism for brain cells, how would a glioblastoma (GBM) lineage behave under ZIKV infection, considering GBM the most common and malignant brain tumor in adults, presenting extreme chemoresistance and high morbidity and mortality rates? The current trend of using genetically engineered oncolytic pathogens as a safe way to eliminate tumors is under development, with trials already in course...
December 28, 2017: Journal of Mass Spectrometry: JMS
https://www.readbyqxmd.com/read/29250483/illuminating-brain-activities-with-fluorescent-protein-based-biosensors
#12
Zhijie Chen, Tan M Truong, Hui-Wang Ai
Fluorescent protein-based biosensors are indispensable molecular tools for life science research. The invention and development of high-fidelity biosensors for a particular molecule or molecular event often catalyze important scientific breakthroughs. Understanding the structural and functional organization of brain activities remain a subject for which optical sensors are in desperate need and of growing interest. Here, we review genetically encoded fluorescent sensors for imaging neuronal activities with a focus on the design principles and optimizations of various sensors...
2017: Chemosensors (Basel, Switzerland)
https://www.readbyqxmd.com/read/29242625/regulation-of-hyperoxia-induced-social-behaviour-in-pristionchus-pacificus-nematodes-requires-a-novel-cilia-mediated-environmental-input
#13
Eduardo Moreno, Bogdan Sieriebriennikov, Hanh Witte, Christian Rödelsperger, James W Lightfoot, Ralf J Sommer
Social behaviours are frequently utilised for defence and stress avoidance in nature. Both Caenorhabditis elegans and Pristionchus pacificus nematodes display social behaviours including clumping and bordering, to avoid hyperoxic stress conditions. Additionally, both species show natural variation in social behaviours with "social" and "solitary" strains. While the single solitary C. elegans N2 strain has evolved under laboratory domestication due to a gain-of-function mutation in the neuropeptide receptor gene npr-1, P...
December 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29231171/tracing-neuronal-circuits-in-transgenic-animals-by-transneuronal-control-of-transcription-tract
#14
Ting-Hao Huang, Peter Niesman, Deepshika Arasu, Daniel Lee, Aubrie De La Cruz, Antuca Callejas, Elizabeth J Hong, Carlos Lois
Understanding the computations that take place in brain circuits requires identifying how neurons in those circuits are connected to one another. We describe a technique called TRACT (TRAnsneuronal Control of Transcription) based on ligand-induced intramembrane proteolysis to reveal monosynaptic connections arising from genetically labeled neurons of interest. In this strategy, neurons expressing an artificial ligand ('donor' neurons) bind to and activate a genetically-engineered artificial receptor on their synaptic partners ('receiver' neurons)...
December 12, 2017: ELife
https://www.readbyqxmd.com/read/29144959/induction-of-innervation-by-encapsulated-adipocytes-with-engineered-vitamin-a-metabolism
#15
Qiwen Shen, Rumana Yasmeen, Jessica Marbourg, Lu Xu, Lianbo Yu, Paolo Fadda, Alan Flechtner, L James Lee, Phillip G Popovich, Ouliana Ziouzenkova
Innervation is a fundamental basis for function and survival of tissues. In the peripheral tissues, degenerative diseases create a neurotoxic metabolic milieu that either causes neurodegeneration or fails to sustain regenerative growth and reinnervation of injured/diseased tissues. Encapsulation of cells producing neurotrophic factors can augment axon growth and neuron survival; however, sustained innervation in vivo requires a combination of factors promoting axon growth and guidance pathway that are released in a tissue-specific context...
October 28, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/29140243/a-versatile-genetic-tool-for-post-translational-control-of-gene-expression-in-drosophila-melanogaster
#16
Sachin Sethi, Jing W Wang
Several techniques have been developed to manipulate gene expression temporally in intact neural circuits. However, the applicability of current tools developed for in vivo studies in Drosophila is limited by their incompatibility with existing GAL4 lines and side effects on physiology and behavior. To circumvent these limitations, we adopted a strategy to reversibly regulate protein degradation with a small molecule by using a destabilizing domain (DD). We show that this system is effective across different tissues and developmental stages...
November 15, 2017: ELife
https://www.readbyqxmd.com/read/29120948/parvalbumin-containing-gaba-cells-and-schizophrenia-experimental-model-based-on-targeted-gene-delivery-through-adeno-associated-viruses
#17
Marta U Woloszynowska-Fraser, Peer Wulff, Gernot Riedel
Understanding the contribution of transmitter systems in behavioural pharmacology has a long tradition. Multiple techniques such as transmitter-specific lesions, and also localized administration of pharmacological toxins including agonists and antagonists of selected receptors have been applied. More recently, modern genetic tools have permitted cell-type selective interferences, for example by expression of light-sensitive channels followed by optogenetic stimulation in behaviourally meaningful settings or by engineered channels termed DREADDS that respond to peripherally administered drugs...
December 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/29097684/anion-conducting-channelrhodopsins-with-tuned-spectra-and-modified-kinetics-engineered-for-optogenetic-manipulation-of-behavior
#18
Jonas Wietek, Silvia Rodriguez-Rozada, Janine Tutas, Federico Tenedini, Christiane Grimm, Thomas G Oertner, Peter Soba, Peter Hegemann, J Simon Wiegert
Genetic engineering of natural light-gated ion channels has proven a powerful way to generate optogenetic tools for a wide variety of applications. In recent years, blue-light activated engineered anion-conducting channelrhodopsins (eACRs) have been developed, improved, and were successfully applied in vivo. We asked whether the approaches used to create eACRs can be transferred to other well-characterized cation-conducting channelrhodopsins (CCRs) to obtain eACRs with a broad spectrum of biophysical properties...
November 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29043563/malformation-of-the-posterior-cerebellar-vermis-is-a-common-neuroanatomical-phenotype-of-genetically-engineered-mice-on-the-c57bl-6-background
#19
Joshua A Cuoco, Anthony W Esposito, Shannon Moriarty, Ying Tang, Sonika Seth, Alyssa R Toia, Elias B Kampton, Yevgeniy Mayr, Mussarah Khan, Mohammad B Khan, Brian R Mullen, James B Ackman, Faez Siddiqi, John H Wolfe, Olga V Savinova, Raddy L Ramos
C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the posterior vermis, indicative of neuronal migration defect during cerebellar development. Recognizing that many genetically engineered (GE) mouse lines are produced from C57BL/6 ES cells or backcrossed to this strain, we performed histological analyses and found that cerebellar heterotopia were a common feature present in the majority of GE lines on this background. Furthermore, we identify GE mouse lines that will be valuable in the study of cerebellar malformations including diverse driver, reporter, and optogenetic lines...
October 17, 2017: Cerebellum
https://www.readbyqxmd.com/read/28911965/physiological-roles-of-cns-muscarinic-receptors-gained-from-knockout-mice
#20
REVIEW
Morgane Thomsen, Gunnar Sørensen, Ditte Dencker
Because the five muscarinic acetylcholine receptor subtypes have overlapping distributions in many CNS tissues, and because ligands with a high degree of selectivity for a given subtype long remained elusive, it has been difficult to determine the physiological functions of each receptor. Genetically engineered knockout mice, in which one or more muscarinic acetylcholine receptor subtype has been inactivated, have been instrumental in identifying muscarinic receptor functions in the CNS, at the neuronal, circuit, and behavioral level...
September 11, 2017: Neuropharmacology
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