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Neurobiology of Disease

Dan Piña-Fuentes, Jonathan C van Zijl, J Marc C van Dijk, Simon Little, Gerd Tinkhauser, D L Marinus Oterdoom, Marina A J Tijssen, Martijn Beudel
INTRODUCTION: Adaptive deep brain stimulation (aDBS) has been applied in Parkinson's disease (PD), based on the presence of brief high-amplitude beta (13-35 Hz) oscillation bursts in the subthalamic nucleus (STN), which correlate with symptom severity. Analogously, average low-frequency (LF) oscillatory power (4-12 Hz) in the internal globus pallidus (GPi) correlates with dystonic symptoms and might be a suitable physiomarker for aDBS in dystonia. Characterization of pallidal bursts could facilitate the implementation of aDBS in the GPi of PD and dystonia patients...
September 15, 2018: Neurobiology of Disease
Hung Nguyen, Sydney Zarriello, Alexandreya Coats, Cannon Nelson, Chase Kingsbury, Anna Gorsky, Mira Rajani, Elliot G Neal, Cesar V Borlongan
Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy...
September 13, 2018: Neurobiology of Disease
Gabriella MacDougall, Ryan S Anderton, Frank L Mastaglia, Neville W Knuckey, Bruno P Meloni
Stroke is the second leading cause of death globally and represents a major cause of devastating long-term disability. Despite sustained efforts to develop clinically effective neuroprotective therapies, presently there is no clinically available neuroprotective agent for stroke. As a central mediator of neurodamaging events in stroke, mitochondria are recognised as a critical neuroprotective target, and as such, provide a focus for developing mitochondrial-targeted therapeutics. In recent years, cationic arginine-rich peptides (CARPs) have been identified as a novel class of neuroprotective agent with several demonstrated mechanisms of action, including their ability to target mitochondria and exert positive effects on the organelle...
September 12, 2018: Neurobiology of Disease
Xiaoyan Jiang, Jun Suenaga, Hongjian Pu, Zhishuo Wei, Amanda D Smith, Xiaoming Hu, Yejie Shi, Jun Chen
Post-stroke treatment with omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be a promising therapy in young animals but this has not been tested in aged subjects, a population at most risk of ischemic stroke. Herein we examined the therapeutic efficacy of n-3 PUFAs after distal middle cerebral artery occlusion (dMCAO) in young (10-12 weeks old) and aged (18 months old) mice. Post-ischemic mice were randomly assigned to 4 groups that received: 1) regular food with low content of n-3 PUFAs, 2) intraperitoneal docosahexaenoic acid (DHA, a major component of n-3 PUFAs) injections, 3) Fish oil (FO, containing high concentration of n-3 PUFAs) dietary supplement, or 4) combined treatment with DHA and FO dietary supplement...
September 12, 2018: Neurobiology of Disease
Najiba Mammadova, Corey M Summers, Robyn D Kokemuller, Qing He, Shaowei Ding, Thierry Baron, Chenxu Yu, Rudy J Valentine, Donald S Sakaguchi, Anumantha G Kanthasamy, Justin J Greenlee, M Heather West Greenlee
Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded α-synuclein within the central nervous system (CNS). Visual problems in PD patients are common, although retinal pathology associated with PD is not well understood. The purpose of this study was to investigate retinal pathology in a transgenic mouse model (TgM83) expressing the human A53T α-synuclein mutation and assess the effect of α-synuclein "seeding" on the development of retinal pathology...
September 12, 2018: Neurobiology of Disease
M A Urbin, Dylan A Royston, Douglas J Weber, Michael L Boninger, Jennifer L Collinger
Motor output maps within primary motor cortex are widely distributed and modified by motor skill learning and neurological injury. Functions that these maps represent after spinal cord injury remain debatable. Moreover, the pattern of reorganization and whether it supports recovery of compromised motor function is not well understood. A deeper understanding of the pathophysiological mechanisms of motor dysfunction after spinal cord injury is necessary to develop and optimize repair strategies. There are three purposes for this review...
September 11, 2018: Neurobiology of Disease
Nadine K Gut, Juan Mena-Segovia
Cholinergic neurons of the pedunculopontine nucleus (PPN) are interconnected with all the basal ganglia structures, as well as with motor centers in the brainstem and medulla. Recent theories put into question whether PPN cholinergic neurons form part of a locomotor region that directly regulates the motor output, and rather suggest a modulatory role in adaptive behavior involving both motor and cognitive functions. In support of this, experimental studies in animals suggest that cholinergic neurons reinforce actions by signaling reward prediction and shape adaptations in behavior during changes in environmental contingencies...
September 10, 2018: Neurobiology of Disease
Lauren K Wareham, Ana C Dordea, Grigorij Schleifer, Vincent Yao, Annabelle Batten, Fei Fei, Joseph Mertz, Meredith Gregory-Ksander, Louis R Pasquale, Rebecca M Sappington, Emmanuel S Buys
The nitric oxide - guanylyl cyclase-1 - cyclic guanylate monophosphate (NO-GC-1-cGMP) pathway has emerged as a potential pathogenic mechanism for glaucoma, a common intraocular pressure (IOP)-related optic neuropathy characterized by the degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve. NO activates GC-1 to increase cGMP levels, which are lowered by cGMP-specific phosphodiesterase (PDE) activity. This pathway appears to play a role in both the regulation of IOP, where reduced cGMP levels in mice leads to elevated IOP and subsequent RGC degeneration...
September 10, 2018: Neurobiology of Disease
Lorena Saelices, Malgorzata Pokrzywa, Katarzyna Pawelek, David S Eisenberg
No abstract text is available yet for this article.
September 10, 2018: Neurobiology of Disease
L Trobiani, F L Favaloro, M A Di Castro, M Di Mattia, M Cariello, E Miranda, S Canterini, M E De Stefano, D Comoletti, C Limatola, A De Jaco
An increasing number of rare mutations linked to autism spectrum disorders have been reported in genes encoding for proteins involved in synapse formation and maintenance, such as the post-synaptic cell adhesion proteins neuroligins. Most of the autism-linked mutations in the neuroligin genes map on the extracellular protein domain. The autism-linked substitution R451C in Neuroligin3 (NLGN3) induces a local misfolding of the extracellular domain, causing defective trafficking and retention of the mutant protein in the endoplasmic reticulum (ER)...
September 7, 2018: Neurobiology of Disease
Ismaël Daher, Bérénice Le Dieu-Lugon, Maryline Lecointre, Nicolas Dupré, Caroline Voisin, Philippe Leroux, Nathalie Dourmap, Bruno J Gonzalez, Stéphane Marret, Isabelle Leroux-Nicollet, Carine Cleren
Cerebral lesions acquired in the perinatal period can induce cerebral palsy (CP), a multifactorial pathology leading to lifelong motor and cognitive deficits. Several risk factors, including perinatal hypoxia-ischemia (HI), can contribute to the emergence of CP in preterm infants. Currently, there is no international consensus on treatment strategies to reduce the risk of developing CP. A meta-analysis showed that magnesium sulfate (MgSO4 ) administration to mothers at risk of preterm delivery reduces the risk of developing CP (Crowther et al...
September 7, 2018: Neurobiology of Disease
Svetlana M Stamatovic, Gabriela Revollar Martinez, Anna Hu, Jenifer Choi, Richard F Keep, Anuska V Andjelkovic
Accumulating evidence suggest that cerebral microvascular disease increases with advancing age and is associated with lacunar stroke, leukoaraiosis, vascular dementia and Alzheimer disease. Increased blood brain barrier (BBB) permeability/leakage takes "center stage" in ongoing age-related vascular/brain parenchymal injury. Although significant effort has been made in defining the gene mutations and risk factors involved in microvascular alterations in vascular dementia and Alzheimer disease, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown...
September 6, 2018: Neurobiology of Disease
Chioma Anidi, Johanna J O'Day, Ross W Anderson, Muhammad Furqan Afzal, Judy Syrkin-Nikolau, Anca Velisar, Helen M Bronte-Stewart
Freezing of gait (FOG) is a devastating axial motor symptom in Parkinson's disease (PD) leading to falls, institutionalization, and even death. The response of FOG to dopaminergic medication and deep brain stimulation (DBS) is complex, variable, and yet to be optimized. Fundamental gaps in the knowledge of the underlying neurobiomechanical mechanisms of FOG render this symptom one of the unsolved challenges in the treatment of PD. Subcortical neural mechanisms of gait impairment and FOG in PD are largely unknown due to the challenge of accessing deep brain circuitry and measuring neural signals in real time in freely-moving subjects...
September 6, 2018: Neurobiology of Disease
Zachary A Sorrentino, Yuxing Xia, Cory Funk, Cara J Riffe, Nicola J Rutherford, Carolina Ceballos Diaz, Amanda N Sacino, Nathan D Price, Todd E Golde, Benoit I Giasson, Paramita Chakrabarty
Mechanisms underlying α-synuclein (αSyn) mediated neurodegeneration are poorly understood. Intramuscular (IM) injection of αSyn fibrils in human A53T transgenic M83+/- mice produce a rapid model of α-synucleinopathy with highly predictable onset of motor impairment. Using varying doses of αSyn seeds, we show that αSyn-induced phenotype is largely dose-independent. We utilized the synchrony of this IM model to explore the temporal sequence of αSyn pathology, neurodegeneration and neuroinflammation. Longitudinal tracking showed that while motor neuron death and αSyn pathology occur within 2 months post IM, astrogliosis appears at a later timepoint, implying neuroinflammation is a consequence, rather than a trigger, in this prionoid model of synucleinopathy...
September 6, 2018: Neurobiology of Disease
Ye Zhao, Shikara Keshiya, Farzaneh Atashrazm, Jianqun Gao, Lars M Ittner, Dario R Alessi, Glenda M Halliday, Yuhong Fu, Nicolas Dzamko
Leucine-rich repeat kinase 2 (LRRK2) is genetically implicated in both familial and sporadic Parkinson's disease (PD). Moreover, LRRK2 has emerged as a compelling therapeutic target for the treatment of PD. Consequently, there is much interest in understanding LRRK2 and its role in PD pathogenesis. LRRK2 is constitutively phosphorylated on two serines, S910 and S935, that are required for interaction of LRRK2 with members of the 14-3-3 family of scaffolding proteins. Pathogenic LRRK2 missense mutations impair the phosphorylation of LRRK2 at these sites, but whether this contributes to PD pathology is unclear...
September 5, 2018: Neurobiology of Disease
Geraldine Kong, Kim-Anh Lê Cao, Louise M Judd, ShanShan Li, Thibault Renoir, Anthony J Hannan
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene, which is expressed ubiquitously throughout the brain and peripheral tissues. Whilst the focus of much research has been on the cognitive, psychiatric and motor symptoms of HD, the extent of peripheral pathology and its potential impact on central symptoms has been less intensely explored. Disruption of the gastrointestinal microbiome (gut dysbiosis) has been recently reported in a number of neurological and psychiatric disorders, and therefore we hypothesized that it might also occur in HD...
September 4, 2018: Neurobiology of Disease
Andreas Nowacki, Salvatore Galati, Janine Ai-Schlaeppi, Claudio Bassetti, Alain Kaelin, Claudio Pollo
The pedunculopontine nucleus (PPN) is a reticular nucleus located in the mesencephalic and upper pontine tegmentum. Initially, characterized by its predominant cholinergic projection neurons, it was associated with the "mesencephalic locomotor region" and "reticular activating system". Furthermore, based on histopathological studies, the PPN was hypothesized to play a role in the manifestation of symptoms in movement disorders such as Parkinson's disease (PD). Since axial symptoms represent unmet needs of PD treatments, a series of pioneering experiments in Parkinsonian monkeys promoted the idea of a potential new target for deep brain stimulation (DBS) and much clinical interest was generated in the following years leading to a number of trials analysing the role of PPN for gait disorders...
September 3, 2018: Neurobiology of Disease
Gopalakrishnan Dhanabalan, Tara Wardi Le Maître, Nenad Bogdanovic, Kanar Alkass, Henrik Druid
Chronic alcohol abuse causes cognitive impairments associated with neurodegeneration and volume loss in the human hippocampus. Here, we hypothesize that alcohol reduces the number of granule cells in the human dentate gyrus and consequently contribute to the observed volume loss. Hippocampal samples were isolated from deceased donors with a history of chronic alcohol abuse and from controls with no alcohol overconsumption. From each case, a sample from the mid-portion of hippocampus was sectioned, immunostained for the neuronal nuclear marker NeuN, and counter stained with hematoxylin...
September 3, 2018: Neurobiology of Disease
Takahiro Seki, Masahiro Sato, Yuki Kibe, Tomoko Ohta, Mutsumi Oshima, Ayumu Konno, Hirokazu Hirai, Yuki Kurauchi, Akinori Hisatsune, Hiroshi Katsuki
Spinocerebellar ataxia type 21 (SCA21) is caused by missense or nonsense mutations of the transmembrane protein 240 (TMEM240). Molecular mechanisms of SCA21 pathogenesis remain unknown because the functions of TMEM240 have not been elucidated. We aimed to reveal the molecular pathogenesis of SCA21 using cell and mouse models that overexpressed the wild-type and SCA21 mutant TMEM240. In HeLa cells, overexpressed TMEM240 localized around large cytoplasmic vesicles. The SCA21 mutation did not affect this localization...
September 2, 2018: Neurobiology of Disease
Naoko Inamura, Momoko Kito, Shinji Go, Soichiro Kishi, Masanori Hosokawa, Kiyofumi Asai, Nobuyuki Takakura, Hirohide Takebayashi, Junko Matsuda, Yasushi Enokido
Krabbe disease (KD), or globoid cell leukodystrophy, is an inherited lysosomal storage disease with leukodystrophy caused by a mutation in the galactosylceramidase (GALC) gene. The majority of patients show the early onset form of KD dominated by cerebral demyelination with apoptotic oligodendrocyte (OL) death. However, the initial pathophysiological changes in developing OLs remain poorly understood. Here, we show that OLs of twitcher mice, an authentic mouse model of KD, exhibited developmental defects and impaired myelin formation in vivo and in vitro...
August 31, 2018: Neurobiology of Disease
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