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Neurobiology of Disease

James C Sears, Woong Jae Choi, Kendal Broadie
Recent work shows Fragile X Mental Retardation Protein (FMRP) drives the translation of very large proteins (>2000 aa) mediating neurodevelopment. Loss of function results in Fragile X syndrome (FXS), the leading heritable cause of intellectual disability (ID) and autism spectrum disorder (ASD). Using the Drosophila FXS disease model, we discover FMRP positively regulates the translation of the very large A-Kinase Anchor Protein (AKAP) Rugose (>3000 aa), homolog of ASD-associated human Neurobeachin (NBEA)...
February 13, 2019: Neurobiology of Disease
J Key, A K Mueller, S Gispert, L Matschke, I Wittig, O Corti, C Münch, N Decher, G Auburger
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear how selective neural circuits become vulnerable and finally undergo atrophy. We attempted to go beyond previous work mostly done in peripheral tumor cells, which identified protein targets of Parkin activity, an ubiquitin E3 ligase...
February 11, 2019: Neurobiology of Disease
Anders Christian Meidahl, Christian K E Moll, Bernadette van Wijk, Alessandro Gulberti, Gerd Tinkhauser, Manfred Westphal, Andreas K Engel, Wolfgang Hamel, Peter Brown, Andrew Sharott
Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinson's disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery...
February 9, 2019: Neurobiology of Disease
Liset Menendez de la Prida, Gilles Huberfeld
Oscillations represent basic operational modes of the human brain. They reflect local field potential activity generated by the laminar arrangement of cell-type specific microcircuits interacting brain-wide under the influence of neuromodulators, endogenous processes and cognitive demands. Under neuropathological conditions, the spatiotemporal structure of physiological brain oscillations is disrupted as recorded by electroencephalography and event-relate potentials. Such rhythmopathies can be used to track microcircuit alterations leading not only to transient pathological activities such as interictal discharges and seizures but also to a range of cognitive co-morbidities...
February 8, 2019: Neurobiology of Disease
Marco de Curtis, Laura Librizzi, Laura Uva, Vadym Gnatkovsky
Focal seizures are triggered by the pathological synchronization of a functionally altered group of neurons. In vivo and in vitro results in rodents and single unit studies in humans suggest that seizure can be initiated by increased activity in interneuronal networks. We review here the data derived from in vitro perparations to describe the function of GABAergic network in different phases of focal seizures. The data demonstrate that GABA-mediated synchronization of interneuronal activity has an active role in shaping focal seizure dynamics...
February 8, 2019: Neurobiology of Disease
Nidhi Sharma, Antonella Tramutola, Chiara Lanzillotta, Andrea Arena, Carla Blarzino, Tommaso Cassano, D Allan Butterfield, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone
Hyper-active GSK-3β favors Tau phosphorylation during the progression of Alzheimer's disease (AD). Akt is one of the main kinases inhibiting GSK-3β and its activation occurs in response to neurotoxic stimuli including, i.e., oxidative stress. Biliverdin reductase-A (BVR-A) is a scaffold protein favoring the Akt-mediated inhibition of GSK-3β. Reduced BVR-A levels along with increased oxidative stress were observed early in the hippocampus of 3xTg-AD mice (at 6 months), thus suggesting that loss of BVR-A could be a limiting factor in the oxidative stress-induced Akt-mediated inhibition of GSK-3β in AD...
February 6, 2019: Neurobiology of Disease
M Lessard-Beaudoin, L Yu-Taeger, M Laroche, E Singer, O Riess, H H P Nguyen, R K Graham
Olfactory dysfunction is observed in several neurological disorders, including Huntington disease (HD), and correlates with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite clear evidence demonstrating olfactory dysfunction in HD patients, only limited details are available in murine models and the underlying mechanisms are unknown. In order to determine if alterations in the olfactory bulb (OB) are observed in HD we assessed OB weight or area from 3 to 12 months of age in the BACHD transgenic lines (TG5 and TG9)...
February 6, 2019: Neurobiology of Disease
Jung Eun Shin, Hongseok Ha, Yoon Ki Kim, Yongcheol Cho, Aaron DiAntonio
Following damage to a peripheral nerve, injury signaling pathways converge in the cell body to generate transcriptional changes that support axon regeneration. Here, we demonstrate that dual leucine zipper kinase (DLK), a central regulator of injury responses including axon regeneration and neuronal apoptosis, is required for the induction of the pro-regenerative transcriptional program in response to peripheral nerve injury. Using a sensory neuron-conditional DLK knockout mouse model, we show a time course for the dependency of gene expression changes on the DLK pathway after sciatic nerve injury...
February 5, 2019: Neurobiology of Disease
Dionisio A Amodeo, Chi-Yu Lai, Omron Hassan, Eran A Mukamel, M Margarita Behrens, Susan B Powell
BACKGROUND: Epidemiological studies suggest that the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia is increased by prenatal exposure to viral or bacterial infection during pregnancy. It is still unclear how activation of the maternal immune response interacts with underlying genetic factors to influence observed ASD phenotypes. METHODS: The current study investigated how maternal immune activation (MIA) in mice impacts gene expression in the frontal cortex in adulthood, and how these molecular changes relate to deficits in cognitive flexibility and increases in repetitive behavior that are prevalent in ASD...
February 1, 2019: Neurobiology of Disease
Roberto Colangeli, Roberto Di Maio, Massimo Pierucci, Gabriele Deidda, Maurizio Casarrubea, Giuseppe Di Giovanni
Endocannabinoids (eCBs) and serotonin (5-HT) play a neuromodulatory role in the central nervous system. Both eCBs and 5-HT regulate neuronal excitability and their pharmacological potentiation has been shown to control seizures in pre-clinical and human studies. Compelling evidence indicates that eCB and 5-HT systems interact to modulate several physiological and pathological brain functions, such as food intake, pain, drug addiction, depression, and anxiety. Nevertheless, there is no evidence of an eCB/5-HT interaction in experimental and human epilepsies, including status epilepticus (SE)...
February 1, 2019: Neurobiology of Disease
Pascale Baden, Cong Yu, Michela Deleidi
While the link between GBA and Parkinson's disease (PD) was initially unexpected, it is now well established that GBA mutations are the most frequent genetic risk for PD. GBA has also been linked to sporadic PD, dementia with Lewy bodies, and ageing. Thus, GBA represents a promising target to counteract brain disease and the age-related decline of lysosomal function. The exact mechanisms involved in the risk of developing PD in GBA mutation carriers are still unclear and research in this field has faced the major challenge of a lack of proper modeling systems...
January 31, 2019: Neurobiology of Disease
J Glykys, E Duquette, N Rahmati, K Duquette, K J Staley
Seizures and brain injury lead to water and Cl- accumulation in neurons. The increase in intraneuronal Cl- concentration ([Cl- ]i ) depolarizes the GABAA reversal potential (EGABA ) and worsens seizure activity. Neocortical neuronal membranes have a low water permeability due to the lack aquaporins necessary to move free water. Instead, neurons use cotransport of ions including Cl- to move water. Thus, increasing the extracellular osmolarity during seizures should result in an outward movement of water and salt, reducing [Cl- ]i and improving GABAA receptor-mediated inhibition...
January 31, 2019: Neurobiology of Disease
Lucia Ricciardi, Mariana Sarchioto, Francesca Morgante
No abstract text is available yet for this article.
January 30, 2019: Neurobiology of Disease
Khaled H Elfakhri, Ihab M Abdallah, Andrew D Brannen, Amal Kaddoumi
Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple dysfunctional pathways. Therefore, a sophisticated treatment strategy that simultaneously targets multiple brain cell types and disease pathways could be advantageous for effective intervention. To elucidate an effective treatment, we developed an in vitro high-throughput screening (HTS) assay to evaluate candidate drugs for their ability to enhance the integrity of the blood-brain barrier (BBB) and improve clearance of amyloid-β (Aβ) using a cell-based BBB model...
January 30, 2019: Neurobiology of Disease
Anthony M Downs, Xueliang Fan, Christine Donsante, H A Jinnah, Ellen J Hess
Trihexyphenidyl, a nonselective muscarinic receptor antagonist, is the small molecule drug of choice for the treatment of DYT1 dystonia, but it is poorly tolerated due to significant side effects. A better understanding of the mechanism of action of trihexyphenidyl is needed for the development of improved treatments. Because DTY1 dystonia is associated with both abnormal cholinergic neurotransmission and abnormal dopamine regulation, we tested the hypothesis that trihexyphenidyl normalizes striatal dopamine release in a mouse model of DYT1 dystonia using ex vivo fast scan cyclic voltammetry and in vivo microdialysis...
January 30, 2019: Neurobiology of Disease
Jing Zhang, Zheng Gang Zhang, Mei Lu, Yi Zhang, Xia Shang, Michael Chopp
The death of mature oligodendrocytes (OLs) leads to demyelination in the central nervous system (CNS) and subsequently to functional deficits. Remyelination requires the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating OLs, which in the CNS with neurodegenerative diseases such as multiple sclerosis (MS), is often inhibited. Among the inhibitors of OPC differentiation are toll-like receptor 2 (TLR2) and interleukin-1 receptor-associated kinase 1 (IRAK1) signaling, and both are negatively regulated by microRNA-146a (miR-146a)...
January 29, 2019: Neurobiology of Disease
Simon A Lowe, Maria M Usowicz, James J L Hodge
Down syndrome (DS) is characterised by abnormal cognitive and motor development, and later in life by progressive Alzheimer's disease (AD)-like dementia, neuropathology, declining motor function and shorter life expectancy. It is caused by trisomy of chromosome 21 (Hsa21), but how individual Hsa21 genes contribute to various aspects of the disorder is incompletely understood. Previous work has demonstrated a role for triplication of the Hsa21 gene DYRK1A in cognitive and motor deficits, as well as in altered neurogenesis and neurofibrillary degeneration in the DS brain, but its contribution to other DS phenotypes is unclear...
January 28, 2019: Neurobiology of Disease
Alba Navarro-Romero, Anna Vázquez-Oliver, Maria Gomis-González, Carlos Garzón-Montesinos, Rafael Falcón-Moya, Antoni Pastor, Elena Martín-García, Nieves Pizarro, Arnau Busquets-Garcia, Jean-Michel Revest, Pier-Vincenzo Piazza, Fátima Bosch, Mara Dierssen, Rafael de la Torre, Antonio Rodríguez-Moreno, Rafael Maldonado, Andrés Ozaita
Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model...
January 25, 2019: Neurobiology of Disease
Joan Kaufman, Souraya Torbey
This paper reviews the literature on the association between experiences of child abuse and neglect and the development of psychoses. It then explores the premise that psychotic patients with a history of maltreatment may comprise a clinically and biological distinct subgroup. The review demonstrates that there is a growing consensus in the field that experiences of child maltreatment contribute to the onset of psychotic symptoms and psychotic disorders. There is also strong support for the premise that patients with psychotic disorders and histories of child maltreatment have distinct clinical characteristics and unique treatment needs, and emerging preliminary data to suggest psychotic patients with a history of maltreatment may comprise a distinct neurobiological subgroup...
January 24, 2019: Neurobiology of Disease
Peter T Nelson, Zsombor Gal, Wang-Xia Wang, Dana M Niedowicz, Sergey C Artiushin, Samuel Wycoff, Angela Wei, Gregory A Jicha, David W Fardo
TDP-43 proteinopathy is very common among the elderly (affecting at least 25% in individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects)...
January 22, 2019: Neurobiology of Disease
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