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Transgenic Models of Behaviour

Xing Guo, XiaoYan Sun, Di Hu, Ya-Juan Wang, Hisashi Fujioka, Rajan Vyas, Sudha Chakrapani, Amit Umesh Joshi, Yu Luo, Daria Mochly-Rosen, Xin Qi
Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains...
2016: Nature Communications
Sriram Jayabal, Lovisa Ljungberg, Alanna J Watt
KEY POINTS: Spinocerebellar ataxia type 6 (SCA6) is a midlife-onset neurodegenerative disease caused by a CACNA1A mutation; CACNA1A is also implicated in cerebellar development. We have previously shown that when disease symptoms are present in midlife in SCA6(84Q/84Q) mice, cerebellar Purkinje cells spike with reduced rate and precision. In contrast, we find that during postnatal development (P10-13), SCA6(84Q/84Q) Purkinje cells spike with elevated rate and precision. Although surplus climbing fibres are linked to ataxia in other mouse models, we found surplus climbing fibre inputs on developing (P10-13) SCA6(84Q/84Q) Purkinje cells when motor deficits were not detected...
August 17, 2016: Journal of Physiology
Jianxun Lei, Barbara Benson, Huy Tran, Solomon F Ofori-Acquah, Kalpna Gupta
Pain is a hallmark feature of sickle cell anemia (SCA) but management of chronic as well as acute pain remains a major challenge. Mouse models of SCA are essential to examine the mechanisms of pain and develop novel therapeutics. To facilitate this effort, we compared humanized homozygous BERK and Townes sickle mice for the effect of gender and age on pain behaviors. Similar to previously characterized BERK sickle mice, Townes sickle mice show more mechanical, thermal, and deep tissue hyperalgesia with increasing age...
2016: PloS One
Lucy H Brunt, Roderick E H Skinner, Karen A Roddy, Natalia M Araujo, Emily J Rayfield, Chrissy L Hammond
OBJECTIVE: There is increasing evidence that joint shape is a potent predictor of osteoarthritis risk; yet the cellular events underpinning joint morphogenesis remain unclear. We sought to develop a genetically tractable animal model to study the events controlling joint morphogenesis. DESIGN: Zebrafish larvae were subjected to periods of flaccid paralysis, rigid paralysis or hyperactivity. Immunohistochemistry and transgenic reporters were used to monitor changes to muscle and cartilage...
June 29, 2016: Osteoarthritis and Cartilage
Aurelia Vernay, Ludivine Therrault, Béatrice Blot, Valérie Risson, Sylvie Dirrig-Grosch, Robin Waegaert, Thiebault Lequeu, François Sellal, Laurent Schaeffer, Rémy Saddoul, Jean-Philippe Loeffler, Frédérique René
Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS-FTD syndrome. To model this syndrome we generated a transgenic mouse line expressing the human CHMP2B(intron5) mutant in a neuron specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2B(intron5) mice died due to generalized paralysis...
June 21, 2016: Human Molecular Genetics
Sowmya Madhavadas, Sarada Subramanian
OBJECTIVE: Several dietary supplements are actively being tested for their dual role of alleviating the metabolic perturbations and restricting the consequent cognitive dysfunctions seen in neurodegenerative disorders such as Alzheimer's disease (AD). The aim of the current study was to assess the influence of aqueous extract of cinnamon (CE) on the monosodium glutamate-induced non-transgenic rat model of AD (NTAD) established with insulin resistance, hyperglycaemia, neuronal loss, and cognitive impairment at a very early stage of life...
June 16, 2016: Nutritional Neuroscience
Marie K Bondulich, Tong Guo, Christopher Meehan, John Manion, Teresa Rodriguez Martin, Jacqueline C Mitchell, Tibor Hortobagyi, Natalia Yankova, Virginie Stygelbout, Jean-Pierre Brion, Wendy Noble, Diane P Hanger
Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications including phosphorylation, ubiquitination and truncation, are characteristic features of tau present in the brain in human tauopathy. We have previously reported an N-terminally truncated form of tau in human brain that is associated with the development of tauopathy and is highly phosphorylated. We have generated a new mouse model of tauopathy in which this human brain-derived, 35 kDa tau fragment (Tau35) is expressed in the absence of any mutation and under the control of the human tau promoter...
August 2016: Brain: a Journal of Neurology
Roua Abulkassim, Ros Brett, Scott M MacKenzie, Trevor J Bushell
Proteinase-activated receptor-2 (PAR2) is widely expressed in the CNS but whether it plays a key role in inflammation-related behavioural changes remains unknown. Hence, in the present study we have examined whether PAR2 contributes to behaviour associated with systemic inflammation using PAR2 transgenic mice. The onset of sickness behaviour was delayed and the recovery accelerated in PAR2(-/-) mice in the LPS-induced model of sickness behaviour. In contrast, PAR2 does not contribute to behaviour under normal conditions...
June 15, 2016: Journal of Neuroimmunology
Pratap Meera, Stefan M Pulst, Thomas S Otis
Degenerative ataxias are a common form of neurodegenerative disease that affect about 20 individuals per 100,000. The autosomal dominant spinocerebellar ataxias (SCAs) are caused by a variety of protein coding mutations (single nucleotide changes, deletions and expansions) in single genes. Affected genes encode plasma membrane and intracellular ion channels, membrane receptors, protein kinases, protein phosphatases and proteins of unknown function. Although SCA-linked genes are quite diverse they share two key features: first, they are highly, although not exclusively, expressed in cerebellar Purkinje neurons (PNs), and second, when mutated they lead ultimately to the degeneration of PNs...
August 15, 2016: Journal of Physiology
Raúl Guillot, Raúl Cortés, Sandra Navarro, Morena Mischitelli, Víctor García-Herranz, Elisa Sánchez, Laura Cal, Juan Carlos Navarro, Jesús M Míguez, Sergey Afanasyev, Aleksei Krasnov, Roger D Cone, Josep Rotllant, Jose Miguel Cerdá-Reverter
Melanocortin signaling is regulated by the binding of naturally occurring antagonists, agouti-signaling protein (ASIP) and agouti-related protein (AGRP) that compete with melanocortin peptides by binding to melanocortin receptors to regulate energy balance and growth. Using a transgenic model overexpressing ASIP, we studied the involvement of melanocortin system in the feeding behaviour, growth and stress response of zebrafish. Our data demonstrate that ASIP overexpression results in enhanced growth but not obesity...
June 2016: Hormones and Behavior
Y Chen, Y Niu, W Ji
Nonhuman primates (NHPs) are superior than rodents to be animal models for the study of human diseases, due to their similarities in terms of genetics, physiology, developmental biology, social behaviour and cognition. Transgenic animals have become a key tool in functional genomics to generate models for human diseases and validate new drugs. However, until now, progress in the field of transgenic NHPs has been slow because of technological limitations. Many human diseases, including neurodegenerative disorders, are caused by mutations in endogenous genes...
September 2016: Journal of Internal Medicine
Elizabeth A Skillings, A Jennifer Morton
BACKGROUND: Impairments in energy metabolism are implicated in Huntington's disease (HD) pathogenesis. Reduced levels of the mitochondrial enzyme succinate dehydrogenase (SDH), the main element of complex II, are observed post mortem in the brains of HD patients, and energy metabolism defects have been identified in both presymptomatic and symptomatic HD patients. OBJECTIVE: Chemical preconditioning with 3-nitropropionic acid (3-NP), an irreversible inhibitor of SDH, has been shown to increase tolerance against experimental hypoxia in both heart and brain...
2016: Journal of Huntington's Disease
Yi Lu, Cheng Zhong, Lulu Wang, Pengfei Wei, Wei He, Kang Huang, Yi Zhang, Yang Zhan, Guoping Feng, Liping Wang
Temporal lobe epilepsy (TLE) is one of the most common drug-resistant forms of epilepsy in adults and usually originates in the hippocampal formations. However, both the network mechanisms that support the seizure spread and the exact directions of ictal propagation remain largely unknown. Here we report the dissection of ictal propagation in the hippocampal-entorhinal cortex (HP-EC) structures using optogenetic methods in multiple brain regions of a kainic acid-induced model of TLE in VGAT-ChR2 transgenic mice...
2016: Nature Communications
Jana Schmidt, Thorsten Schmidt, Matthias Golla, Lisa Lehmann, Jonasz Jeremiasz Weber, Jeannette Hübener-Schmid, Olaf Riess
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder for which no curative therapy is available. The cause of this disease is the expansion of a CAG repeat in the so-called ATXN3 gene leading to an expanded polyglutamine stretch in the ataxin-3 protein. Although the function of ataxin-3 has been defined as a deubiquitinating enzyme, the pathogenic pathway underlying SCA3 remains to be deciphered. Besides others, also the glutamatergic system seems to be altered in SCA3...
July 2016: Journal of Neurochemistry
David J Koss, Lianne Robinson, Benjamin D Drever, Kaja Plucińska, Sandra Stoppelkamp, Peter Veselcic, Gernot Riedel, Bettina Platt
Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau...
July 2016: Neurobiology of Disease
Véréna Landel, Pascal Millet, Kévin Baranger, Béatrice Loriod, François Féron
BACKGROUND: Increasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer's disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates...
2016: Molecular Neurodegeneration
Susanna Mantovani, Richard Gordon, Rui Li, Daniel C Christie, Vinod Kumar, Trent M Woodruff
Huntington's disease (HD) is an incurable neurodegenerative condition characterized by progressive motor and cognitive dysfunction, and depletion of neurons in the striatum. Recently, BACHD transgenic mice expressing the full-length human huntingtin gene have been generated, which recapitulate some of the motor and cognitive deficits seen in HD. In this study, we carried out a series of extensive behavioural and neuropathological tests on BACHD mice, to validate this mouse for preclinical research. Transgenic C57BL/6J BACHD and litter-matched wild-type mice were examined in a battery of motor and cognitive function tests at regular intervals up to 12 months of age...
May 1, 2016: Human Molecular Genetics
Paloma Vicens, Luis Heredia, Margarita Torrente, José L Domingo
BACKGROUND: Cholinergic deficits play an important role in both cognitive and behavioural alterations in Alzheimer's disease. This study was aimed at evaluating the possible therapeutic role of PNU-282987 (PNU), an α7 nicotinic cholinergic receptor agonist, and the possible effects of stress in precipitating the onset of behavioural deficits in animals with susceptibility to Alzheimer's disease. METHODS: B6C3-Tg mice with susceptibility to Alzheimer's disease and wild-type mice either with or without restraint stress received 0- or 1-mg/kg PNU...
January 27, 2016: Psychogeriatrics: the Official Journal of the Japanese Psychogeriatric Society
Zhen Liu, Xiao Li, Jun-Tao Zhang, Yi-Jun Cai, Tian-Lin Cheng, Cheng Cheng, Yan Wang, Chen-Chen Zhang, Yan-Hong Nie, Zhi-Fang Chen, Wen-Jie Bian, Ling Zhang, Jianqiu Xiao, Bin Lu, Yue-Fang Zhang, Xiao-Di Zhang, Xiao Sang, Jia-Jia Wu, Xiu Xu, Zhi-Qi Xiong, Feng Zhang, Xiang Yu, Neng Gong, Wen-Hao Zhou, Qiang Sun, Zilong Qiu
Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression...
February 4, 2016: Nature
Adrian Olmos-Alonso, Sjoerd T T Schetters, Sarmi Sri, Katharine Askew, Renzo Mancuso, Mariana Vargas-Caballero, Christian Holscher, V Hugh Perry, Diego Gomez-Nicola
The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity...
March 2016: Brain: a Journal of Neurology
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