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Neurobiology of Disease

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https://www.readbyqxmd.com/read/27913291/a-saposin-deficiency-model-in-drosophila-lysosomal-storage-progressive-neurodegeneration-and-sensory-physiological-decline
#1
Samantha J Hindle, Sarita Hebbar, Dominik Schwudke, Christopher J Elliott, Sean T Sweeney
Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases that mediate the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence or impaired function of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids...
November 29, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27913290/early-and-brain-region-specific-decrease-of-de-novo-cholesterol-biosynthesis-in-huntington-s-disease-a-cross-validation-study-in-q175-knock-in-mice
#2
Mahalakshmi Shankaran, Eleonora Di Paolo, Valerio Leoni, Claudio Caccia, Costanza Ferrari Bardile, Hussein Mohammed, Stefano Di Donato, Seung Kwak, Deanna Marchionini, Scott Turner, Elena Cattaneo, Marta Valenza
Cholesterol precursors and cholesterol levels are reduced in brain regions of Huntington's disease (HD) mice. Here we quantified the rate of in vivo de novo cholesterol biosynthesis in the HD brain. Samples from different brain regions and blood of the heterozygous knock-in mouse model carrying 175 CAG repeats (Q175) at different phenotypic stages were processed independently by two research units to quantify cholesterol synthesis rate by (2)H2O labeling and measure the concentrations of lathosterol, cholesterol and its brain-specific cholesterol catabolite 24-hydroxy-cholesterol (24OHC) by isotope dilution mass spectrometry...
November 29, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27890709/role-of-major-and-brain-specific-sgce-isoforms-in-the-pathogenesis-of-myoclonus-dystonia-syndrome
#3
Jianfeng Xiao, Satya R Vemula, Yi Xue, Mohammad M Khan, Francesca A Carlisle, Adrian J Waite, Derek J Blake, Ioannis Dragatsis, Yu Zhao, Mark S LeDoux
Loss-of-function mutations in SGCE, which encodes ε-sarcoglycan (ε-SG), cause myoclonus-dystonia syndrome (OMIM159900, DYT11). A "major" ε-SG protein derived from CCDS5637.1 (NM_003919.2) and a "brain-specific" protein, that includes sequence derived from alternative exon 11b (CCDS47642.1, NM_001099400.1), are reportedly localized in post- and pre-synaptic membrane fractions, respectively. Moreover, deficiency of the "brain-specific" isoform and other isoforms derived from exon 11b may be central to the pathogenesis of DYT11...
November 24, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27890708/fbxl18-targets-lrrk2-for-proteasomal-degradation-and-attenuates-cell-toxicity
#4
Xiaodong Ding, Sandeep K Barodia, Lisha Ma, Matthew S Goldberg
Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD) and LRRK2 polymorphisms are associated with increased risk for idiopathic PD. However, the molecular mechanisms by which these mutations cause PD remain uncertain. In vitro studies indicate that disease-linked mutations in LRRK2 increase LRRK2 kinase activity and LRRK2-mediated cell toxicity. Identifying LRRK2-interacting proteins and determining their effects on LRRK2 are important for understanding LRRK2 function and for delineating the pathophysiological mechanisms of LRRK2 mutations...
November 24, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27890673/functional-validation-of-abhd12-mutations-in-the-neurodegenerative-disease-pharc
#5
Angèle Tingaud-Sequeira, Demetrio Raldúa, Julie Lavie, Guilaine Mathieu, Magali Bordier, Anja Knoll-Gellida, Pierre Rambeau, Isabelle Coupry, Michèle André, Eva Malm, Claes Möller, Sten Andreasson, Nanna D Rendtorff, Lisbeth Tranebjærg, Michel Koenig, Didier Lacombe, Cyril Goizet, Patrick J Babin
ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid pathways, its precise functional role(s) leading to PHARC disease had not previously been characterized. Cell and zebrafish models were designed to demonstrate the causal link between an identified new missense mutation p...
November 23, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27890672/epigenetics-of-cell-fate-reprogramming-and-its-implications-for-neurological-disorders-modelling
#6
REVIEW
Maciej Grzybek, Aleksandra Golonko, Marta Walczak, Pawel Lisowski
The reprogramming of human induced pluripotent stem cells (hiPSCs) proceeds in a stepwise manner with reprogramming factors binding and epigenetic composition changes during transition to maintain the epigenetic landscape, important for pluripotency. There arises a question as to whether the aberrant epigenetic state after reprogramming leads to epigenetic defects in induced stem cells causing unpredictable long term effects in differentiated cells. In this review, we present a comprehensive view of epigenetic alterations accompanying reprogramming, cell maintenance and differentiation as factors that influence applications of hiPSCs in stem cell based technologies...
November 23, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27888137/the-role-of-rhoa-in-retrograde-neuronal-death-and-axon-regeneration-after-spinal-cord-injury
#7
Jianli Hu, Guixin Zhang, William Rodemer, Li-Qing Jin, Michael Shifman, Michael E Selzer
Paralysis following spinal cord injury (SCI) is due to interruption of axons and their failure to regenerate. It has been suggested that the small GTPase RhoA may be an intracellular signaling convergence point for several types of growth-inhibiting extracellular molecules. Even if this is true in vitro, it is not clear from studies in mammalian SCI, whether the effects of RhoA manipulations on axon growth in vivo are due to a RhoA-mediated inhibition of true regeneration or only of collateral sprouting from spared axons, since work on SCI generally is performed with partial injury models...
November 22, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27884724/optogenetic-stimulation-of-glutamatergic-neuronal-activity-in-the-striatum-enhances-neurogenesis-in-the-subventricular-zone-of-normal-and-stroke-mice
#8
Mingke Song, Shan Ping Yu, Osama Mohamad, Wenyuan Cao, Zheng Zachory Wei, Xiaohuan Gu, Michael Qize Jiang, Ling Wei
Neurogenesis in the subventricular zone (SVZ) of the adult brain may contribute to tissue repair after brain injuries. Whether SVZ neurogenesis can be upregulated by specific neuronal activity in vivo and promote functional recovery after stroke is largely unknown. Using the spatial and cell type specific optogenetic technique combined with multiple approaches of in vitro, ex vivo and in vivo examinations, we tested the hypothesis that glutamatergic activation in the striatum could upregulate SVZ neurogenesis in the normal and ischemic brain...
November 21, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27852007/apc-conditional-knock-out-mouse-is-a-model-of-infantile-spasms-with-elevated-neuronal-%C3%AE-catenin-levels-neonatal-spasms-and-chronic-seizures
#9
Antonella Pirone, Jon Alexander, Lauren A Lau, David Hampton, Andrew Zayachkivsky, Amy Yee, Audrey Yee, Michele H Jacob, Chris G Dulla
Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life. The molecular causes of IS are poorly defined. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter β-catenin pathways. However, evidence linking malfunction of β-catenin pathways and IS is lacking. Here, we show that conditional deletion in mice of the adenomatous polyposis coli gene (APC cKO), the major negative regulator of β-catenin, leads to excessive β-catenin levels and multiple salient features of human IS...
November 13, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27818324/the-sigma-1-receptor-mediates-the-beneficial-effects-of-pridopidine-in-a-mouse-model-of-huntington-disease
#10
Daniel Ryskamp, Jun Wu, Michal Geva, Rebecca Kusko, Iris Grossman, Michael Hayden, Ilya Bezprozvanny
The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated "dopamine stabilizer", has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD...
November 3, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27818323/als-causing-mutations-differentially-affect-pgc-1%C3%AE-expression-and-function-in-the-brain-vs-peripheral-tissues
#11
Hanna Bayer, Kerstin Lang, Eva Buck, Julia Higelin, Lara Barteczko, Noemi Pasquarelli, Jasmin Sprissler, Tanja Lucas, Karlheinz Holzmann, Maria Demestre, Katrin S Lindenberg, Karin M Danzer, Tobias Boeckers, Albert C Ludolph, Luc Dupuis, Patrick Weydt, Anke Witting
BACKGROUND: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α). METHODS: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations...
November 3, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27816769/in-vivocharacterization-of-the-aspartyl-trna-synthetase-dars-homing-in-on-the-leukodystrophy-hbsl
#12
Dominik Fröhlich, Alexandra K Suchowerska, Ziggy H T Spencer, Georg von Jonquieres, Claudia B Klugmann, Andre Bongers, Fabien Delerue, Holly Stefen, Lars M Ittner, Thomas Fath, Gary D Housley, Matthias Klugmann
BACKGROUND: The recently diagnosed leukodystrophy Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity (HBSL) is caused by mutations of the cytoplasmic aspartyl-tRNA synthetase geneDARS. The physiological role of DARS in translation is to accurately pair aspartate with its cognate tRNA. Clinically, HBSL subjects show a distinct pattern of hypomyelination and develop progressive leg spasticity, variable cognitive impairment and epilepsy. To elucidate the underlying pathomechanism, we comprehensively assessed endogenous DARS expression in mice...
November 2, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27816768/human-immunodeficiency-virus-protein-tat-induces-oligodendrocyte-injury-by-enhancing-outward-k-current-conducted-by-kv1-3
#13
Han Liu, Jianuo Liu, Enquan Xu, Guihua Tu, Minglei Guo, Shangdong Liang, Huangui Xiong
Brain white matter damage is frequently detected in patients infected with human immunodeficiency virus type 1 (HIV-1). White matter is composed of neuronal axons sheathed by oligodendrocytes (Ols), the myelin-forming cells in central nervous system. Ols are susceptible to HIV-1 viral trans-activator of transcription (Tat) and injury of Ols results in myelin sheath damage. It has been demonstrated that activation of voltage-gated K(+) (KV) channels induces cell apoptosis and Ols predominantly express K(+) channel KV1...
November 2, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27793638/tau-hyperphosphorylation-in-the-brain-of-ob-ob-mice-is-due-to-hypothermia-importance-of-thermoregulation-in-linking-diabetes-and-alzheimer-s-disease
#14
Maud Gratuze, Noura B El Khoury, Andréanne Turgeon, Carl Julien, François Marcouiller, Françoise Morin, Robert A Whittington, André Marette, Frédéric Calon, Emmanuel Planel
Over the last few decades, there has been a significant increase in epidemiological studies suggesting that type 2 diabetes (T2DM) is linked to a higher risk of Alzheimer's disease (AD). However, how T2DM affects AD pathology, such as tau hyperphosphorylation, is not well understood. In this study, we investigated the impact of T2DM on tau phosphorylation in ob/ob mice, a spontaneous genetic model of T2DM. Tau phosphorylation at the AT8 epitope was slightly elevated in 4-week-old ob/ob mice while 26-week-old ob/ob mice exhibited tau hyperphosphorylation at multiple tau phospho-epitopes (Tau1, CP13, AT8, AT180, PHF1)...
October 26, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27793637/morphometric-alterations-of-golgi-apparatus-in-alzheimer-s-disease-are-related-to-tau-hyperphosphorylation
#15
Alejandro Antón-Fernández, Guillermo Aparicio-Torres, Silvia Tapia, Javier DeFelipe, Alberto Muñoz
The Golgi apparatus (GA) is a highly dynamic organelle, which is mainly involved in the post-translational processing and targeting of cellular proteins and which undergoes significant morphological changes in response to different physiological and pathological conditions. In the present study, we have analyzed the possible alterations of GA in neurons from the temporal neocortex and hippocampus of Alzheimer's disease (AD) patients, using double immunofluorescence techniques, confocal microscopy and 3D quantification techniques...
October 26, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27765583/cisplatin-induces-mitochondrial-deficits-in-drosophila-larval-segmental-nerve
#16
Jewel L Podratz, Han Lee, Patrizia Knorr, Stephanie Koehler, Steven Forsythe, Kelsey Lambrecht, Suzette Arias, Kiley Schmidt, Gabrielle Steinhoff, Georgiy Yudintsev, Amy Yang, Eugenia Trushina, Anthony Windebank
Cisplatin is an effective chemotherapy drug that induces peripheral neuropathy in cancer patients. In rodent dorsal root ganglion neurons, cisplatin binds nuclear and mitochondrial DNA (mtDNA) inducing DNA damage and apoptosis. Platinum-mtDNA adducts inhibit mtDNA replication and transcription leading to mitochondrial degradation. Cisplatin also induces climbing deficiencies associated with neuronal apoptosis in adult Drosophila melanogaster. Here we used Drosophila larvae that express green fluorescent protein in the mitochondria of motor neurons to observe the effects of cisplatin on mitochondrial dynamics and function...
October 17, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27717882/pain-modulation-from-the-brain-during-diabetic-neuropathy-uncovering-the-role-of-the-rostroventromedial-medulla
#17
Marta Silva, José Tiago Costa-Pereira, Daniel Martins, Isaura Tavares
Diabetic neuropathy has a profound impact in the quality of life of patients who frequently complain of pain. The mechanisms underlying diabetic neuropathic pain (DNP) are no longer ascribed only to damage of peripheral nerves. The effects of diabetes at the central nervous system are currently considered causes of DPN. Management of DNP may be achieved by antidepressants that act on serotonin (5-HT) uptake, namely specific serotonin reuptake inhibitors. The rostroventromedial medulla (RVM) is a key pain control center involved in descending pain modulation at the spinal cord through local release of 5-HT and plays a peculiar role in the balance of bidirectional control (i...
October 4, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27697537/macrophages-are-essential-for-maintaining-a-m2-protective-response-early-after-ischemic-brain-injury
#18
Carlo Perego, Stefano Fumagalli, Elisa R Zanier, Erika Carlino, Nicolò Panini, Eugenio Erba, Maria-Grazia De Simoni
Resident microglia and recruited macrophages are major contributors to the post-ischemic inflammatory response. Initially considered functionally homogeneous populations, data now suggest distinct but still controversial roles after brain injury. Using a model of conditional monocyte/macrophage depletion we studied the contribution of these myeloid cells to brain lesion progression after ischemia, and their influence on the ischemic inflammatory environment. Male CD11b-DTR transgenic mice, expressing the human diphtheria toxin receptor under the control of the CD11b promoter, were treated with diphtheria toxin to induce monocyte/macrophage depletion...
September 30, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27693510/characterization-of-novel-dystonia-musculorum-mutant-mice-implications-for-central-nervous-system-abnormality
#19
Masao Horie, Kazuyuki Mekada, Hiromi Sano, Yoshiaki Kikkawa, Satomi Chiken, Takuro Someya, Keisuke Saito, M Ibrahim Hossain, Masaaki Nameta, Kuniya Abe, Kenji Sakimura, Katsuhiko Ono, Atsushi Nambu, Atsushi Yoshiki, Hirohide Takebayashi
We identified a novel spontaneous mutant mouse showing motor symptoms that are similar to those of the dystonia musculorum (dt) mouse. The observations suggested that the mutant mice inherited the mild dt phenotype as an autosomal recessive trait. Linkage analysis showed that the causative gene was located near D1Mit373 and D1Mit410 microsatellite markers on chromosome 1, which are close to the dystonin (Dst) gene locus. To investigate whether Dst is the causative gene of the novel mutant phenotype, we crossed the mutant with Dst gene trap (Dst(Gt)) mice...
September 28, 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27663142/rna-binding-disturbances-as-a-continuum-from-spinocerebellar-ataxia-type-2-to-parkinson-disease
#20
Aurore Nkiliza, Eugénie Mutez, Clémence Simonin, Frédéric Leprêtre, Aurélie Duflot, Martin Figeac, Céline Villenet, Pierre Semaille, Thomas Comptdaer, Alexandre Genet, Bernard Sablonnière, David Devos, Luc Defebvre, Alain Destée, Marie-Christine Chartier-Harlin
CAG triplet expansions in Ataxin-2 gene (ATXN2) cause spinocerebellar ataxia type 2 and have a role that remains to be clarified in Parkinson's disease (PD). To study the molecular events associated with these expansions, we sequenced them and analyzed the transcriptome from blood cells of controls and three patient groups diagnosed with spinocerebellar ataxia type 2 (herein referred to as SCA2c) or PD with or without ATXN2 triplet expansions (named SCA2p). The transcriptome profiles of these 40 patients revealed three main observations: i) a specific pattern of pathways related to cellular contacts, proliferation and differentiation associated with SCA2p group, ii) similarities between the SCA2p and sporadic PD groups in genes and pathways known to be altered in PD such as Wnt, Ephrin and Leukocyte extravasation signaling iii) RNA metabolism disturbances with "RNA-binding" and "poly(A) RNA-binding" as a common feature in all groups...
September 20, 2016: Neurobiology of Disease
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