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Neurobiology
Bassoon Controls Presynaptic Autophagy through Atg5
Feb 23, 2017   Neuron
Okerlund ND, Schneider K, Leal-Ortiz S, Montenegro-Venegas C, Kim SA, Garner LC, Gundelfinger ED, Reimer RJ, Garner CC
Bassoon Controls Presynaptic Autophagy through Atg5
Feb 23, 2017
Neuron
Mechanisms regulating the surveillance and clearance of synaptic proteins are not well understood. Intriguingly, the loss of the presynaptic active zone proteins Piccolo and Bassoon triggers the loss of synaptic vesicles (SVs) and compromises synaptic integrity. Here we report that the destruction of SVs in boutons lacking Piccolo and Bassoon was associated with the induction of presynaptic autophagy, a process that depended on poly-ubiquitination, but not the E3 ubiquitin ligase Siah1. Surprisingly, gain or loss of function (LOF) of Bassoon alone suppressed or enhanced presynaptic autophagy, respectively, implying a fundamental role for Bassoon in the local regulation of presynaptic autophagy. Mechanistically, Bassoon was found to interact with Atg5, an E3-like ligase essential for autophagy, and to inhibit the induction of autophagy in heterologous cells. Importantly, Atg5 LOF as well as targeting an Atg5-binding peptide derived from Bassoon inhibited presynaptic autophagy in boutons lacking Piccolo and Bassoon, providing insights into the molecular mechanisms regulating presynaptic autophagy.Copyright © 2017 Elsevier Inc. All rights reserved.
Effects of tDCS on motor learning and memory formation: A consensus and critical position paper
Feb 23, 2017   Clinical Neurophysiology : Official Journal Of The International Federation Of Clinical Neurophysiology
Buch ER, Santarnecchi E, Antal A, Born J, Celnik PA,   . . . . . .   , Sandrini M, Schambra HM, Wassermann EM, Ziemann U, Cohen LG
Effects of tDCS on motor learning and memory formation: A consensus and critical position paper
Feb 23, 2017
Clinical Neurophysiology : Official Journal Of The International Federation Of Clinical Neurophysiology
Motor skills are required for activities of daily living. Transcranial direct current stimulation (tDCS) applied in association with motor skill learning has been investigated as a tool for enhancing training effects in health and disease. Here, we review the published literature investigating whether tDCS can facilitate the acquisition, retention or adaptation of motor skills. Work in multiple laboratories is underway to develop a mechanistic understanding of tDCS effects on different forms of learning and to optimize stimulation protocols. Efforts are required to improve reproducibility and standardization. Overall, reproducibility remains to be fully tested, effect sizes with present techniques vary over a wide range, and the basis of observed inter-individual variability in tDCS effects is incompletely understood. It is recommended that future studies explicitly state in the Methods the exploratory (hypothesis-generating) or hypothesis-driven (confirmatory) nature of the experimental designs. General research practices could be improved with prospective pre-registration of hypothesis-based investigations, more emphasis on the detailed description of methods (including all pertinent details to enable future modeling of induced current and experimental replication), and use of post-publication open data repositories. A checklist is proposed for reporting tDCS investigations in a way that can improve efforts to assess reproducibility.Copyright © 2017. Published by Elsevier B.V.
Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord
Feb 23, 2017   Neuron
Sun S, Xu Q, Guo C, Guan Y, Liu Q, Dong X
Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord
Feb 23, 2017
Neuron
Coding of itch versus pain has been heatedly debated for decades. However, the current coding theories (labeled line, intensity, and selectivity theory) cannot accommodate all experimental observations. Here we identified a subset of spinal interneurons, labeled by gastrin-releasing peptide (Grp), that receive direct synaptic input from both pain and itch primary sensory neurons. When activated, these GrpCopyright © 2017 Elsevier Inc. All rights reserved.
Different Modes of Visual Integration in the Lateral Geniculate Nucleus Revealed by Single-Cell-Initiated Transsynaptic Tracing
Feb 23, 2017   Neuron
Rompani SB, Müllner FE, Wanner A, Zhang C, Roth CN, Yonehara K, Roska B
Different Modes of Visual Integration in the Lateral Geniculate Nucleus Revealed by Single-Cell-Initiated Transsynaptic Tracing
Feb 23, 2017
Neuron
The thalamus receives sensory input from different circuits in the periphery. How these sensory channels are integrated at the level of single thalamic cells is not well understood. We performed targeted single-cell-initiated transsynaptic tracing to label the retinal ganglion cells that provide input to individual principal cells in the mouse lateral geniculate nucleus (LGN). We identified three modes of sensory integration by single LGN cells. In the first, 1-5 ganglion cells of mostly the same type converged from one eye, indicating a relay mode. In the second, 6-36 ganglion cells of different types converged from one eye, revealing a combination mode. In the third, up to 91 ganglion cells converged from both eyes, revealing a binocular combination mode in which functionally specialized ipsilateral inputs joined broadly distributed contralateral inputs. Thus, the LGN employs at least three modes of visual input integration, each exhibiting different degrees of specialization.Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Best practices in data analysis and sharing in neuroimaging using MRI
Feb 23, 2017   Nature Neuroscience Add nature.com free-link Cancel
Nichols TE, Das S, Eickhoff SB, Evans AC, Glatard T,   . . . . . .   , Proal E, Thirion B, Van Essen DC, White T, Yeo BT
Best practices in data analysis and sharing in neuroimaging using MRI
Feb 23, 2017
Nature Neuroscience
Given concerns about the reproducibility of scientific findings, neuroimaging must define best practices for data analysis, results reporting, and algorithm and data sharing to promote transparency, reliability and collaboration. We describe insights from developing a set of recommendations on behalf of the Organization for Human Brain Mapping and identify barriers that impede these practices, including how the discipline must change to fully exploit the potential of the world's neuroimaging data.
Selective ligands for Na
Feb 24, 2017   Neuropharmacology
Chakraborty D, Fedorova OV, Bagrov AY, Kaphzan H
Selective ligands for Na
Feb 24, 2017
Neuropharmacology
Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane physiology by direct electrogenic activity. It determines cellular excitability and synaptic neurotransmission, thus affecting learning and memory processes. A principle catalytic α subunit of NaKA has development-specific expression pattern. There are two α isoforms, α1 and α3, in adult brain neurons. Although NaKA is a housekeeping enzyme, the physiological differences between these two α isoforms in different brain regions have not been well explored. Endogenous cardiotonic steroids, including Marinobufagenin and Ouabain, control the cell homeostasis and cell functions via inhibiting NaKA. Here we employed selective inhibition of α1 and α3 NaKA isoforms by Marinobufagenin and Ouabain respectively, to measure the contribution of α subunits in cellular physiology of three distinct mouse brain regions. The results of the whole cell recording demonstrated that α1 isoform predominated in layer-5 pyramidal cells at rostral motor cortex, while α3 isoform governed the pyramidal neurons at hippocampal CA1 region and to a lesser extent the layer-5 pyramidal neurons of parietal cortex. Furthermore, selective α isoform inhibition induced differential effects on distinct physiological properties even within the same brain region. In addition, our results supported the existence of synergism between two NaKA α isoforms. To conclude, this systematic study of NaKA α isoforms demonstrated their broader roles in neuronal functioning in a region-specific manner.Copyright © 2017. Published by Elsevier Ltd.
Yeast models of Parkinson's disease-associated molecular pathologies
Feb 24, 2017   Current Opinion In Genetics & Development
Tenreiro S, Franssens V, Winderickx J, Outeiro TF
Yeast models of Parkinson's disease-associated molecular pathologies
Feb 24, 2017
Current Opinion In Genetics & Development
The aging of the human population is resulting in an increase in the number of people afflicted by neurodegenerative disorders such as Parkinson's disease (PD), creating tremendous socio-economic challenges. This requires the urgent for the development of effective therapies, and of tools for early diagnosis of the disease. However, our understanding of the molecular mechanisms underlying PD pathogenesis is still incomplete, hampering progress in those areas. In recent years, the progression made in genetics has considerably contributed to our knowledge, by identifying several novel PD genes. Furthermore, many cellular and animal models have proven their value to decipher pathways involved in PD development. In this review we highlight the value of the yeast Saccharomyces cerevisiae as a model for PD. This unicellular eukaryote has contributed to our understanding of the cellular mechanisms targeted by most important PD genes and offers an excellent tool for discovering novel players via powerful and informative high throughput screens that accelerate further validation in more complex models.Copyright © 2017 Elsevier Ltd. All rights reserved.
Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials
Feb 24, 2017   Movement Disorders : Official Journal Of The Movement Disorder Society
Espay AJ, Schwarzschild MA, Tanner CM, Fernandez HH, Simon DK,   . . . . . .   , Kieburtz K, Woo D, Macklin EA, Standaert DG, Lang AE
Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials
Feb 24, 2017
Movement Disorders : Official Journal Of The Movement Disorder Society
Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. © 2017 International Parkinson and Movement Disorder Society.© 2017 International Parkinson and Movement Disorder Society.
Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome
Feb 24, 2017   Movement Disorders : Official Journal Of The Movement Disorder Society
Ariza J, Rogers H, Hartvigsen A, Snell M, Dill M, Judd D, Hagerman P, Martínez-Cerdeño V
Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome
Feb 24, 2017
Movement Disorders : Official Journal Of The Movement Disorder Society
BACKGROUND: Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome pathology includes dystrophic white matter and intranuclear inclusions in neurons and astrocytes. We previously demonstrated that the transport of iron into the brain is altered in fragile X-associated tremor/ataxia syndrome; therefore, we also expect an alteration of iron metabolism in brain areas related to motor control. Iron is essential for cell metabolism, but uncomplexed iron leads to oxidative stress and contributes to the development of neurodegenerative diseases. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome. METHODS: We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome and 9 control cases to study iron localization using Perl's method, and iron-binding proteins using immunostaining. RESULTS: We found increased iron deposition in neuronal and glial cells in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. CONCLUSIONS: Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.
Integrated Organotypic Slice Cultures and RT-QuIC (OSCAR) Assay: Implications for Translational Discovery in Protein Misfolding Diseases
Feb 24, 2017   Scientific Reports
Kondru N, Manne S, Greenlee J, West Greenlee H, Anantharam V, Halbur P, Kanthasamy A, Kanthasamy A
Integrated Organotypic Slice Cultures and RT-QuIC (OSCAR) Assay: Implications for Translational Discovery in Protein Misfolding Diseases
Feb 24, 2017
Scientific Reports
Protein misfolding is a key pathological event in neurodegenerative diseases like prion diseases, synucleinopathies, and tauopathies that are collectively termed protein misfolding disorders. Prions are a prototypic model to study protein aggregation biology and therapeutic development. Attempts to develop anti-prion therapeutics have been impeded by the lack of screening models that faithfully replicate prion diseases and the lack of rapid, sensitive biological screening systems. Therefore, a sensitive model encompassing prion replication and neurotoxicity would be indispensable to the pursuit of intervention strategies. We present an ultra-sensitive screening system coupled to an ex vivo prion organotypic slice culture model to rapidly advance rationale-based high-throughput therapeutic strategies. This hybrid Organotypic Slice Culture Assay coupled with RT-QuIC (OSCAR) permits sensitive, specific and quantitative detection of prions from an infectious slice culture model on a reduced time scale. We demonstrate that the anti-prion activity of test compounds can be readily resolved based on the power and kinetics of seeding activity in the OSCAR screening platform and that the prions generated in slice cultures are biologically active. Collectively, our results imply that OSCAR is a robust model of prion diseases that offers a promising platform for understanding prion proteinopathies and advancing anti-prion therapeutics.
Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy
Feb 24, 2017   Scientific Reports
Wobst HJ, Denk F, Oliver PL, Livieratos A, Taylor TN, Knudsen MH, Bengoa-Vergniory N, Bannerman D, Wade-Martins R
Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy
Feb 24, 2017
Scientific Reports
The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human MAPT locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous Mapt-/- background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.
Novel and functional ATG12 gene variants in sporadic Parkinson's disease
Feb 23, 2017   Neuroscience Letters
Li Y, Huang J, Pang S, Wang H, Zhang A, Hawley RG, Yan B
Novel and functional ATG12 gene variants in sporadic Parkinson's disease
Feb 23, 2017
Neuroscience Letters
Parkinson's disease (PD) is a common and progressive neurodegenerative disease, including familial and sporadic cases. To date, genetic causes for sporadic PD, majority of PD cases, remain largely unknown. Accumulating evidence indicates that dysfunctional autophagy, a highly conserved cellular process, is involved in the PD pathogenesis. We speculated that changed expression levels of autophagy-related genes (ATG) may contribute to PD development. Previously, we have genetically analyzed ATG5 and ATG7 genes in sporadic PD patients and identified several functional DNA sequence variants (DSVs). In groups of sporadic PD patients and ethic-matched healthy controls in this study, we further genetically and functionally analyzed the promoter of ATG12, a critical gene for autophagososme formation. The results showed that three DNA sequence variants (DSVs), g.115842507G>T, g.115842394C>T and g.115841817_18del, were identified three PD patients, which significantly altered transcriptional activity of ATG12 gene promoter, probably due to abolishing or creating binding sites for transcription factors. The transcriptional activity of ATG12 gene promoter was not significantly affected by other two DSVs identified in PD patients, g.115842640A>C and g.115842242G>C, which may not alter binding sites for transcription factors. Therefore, these three functional DSVs identified in PD patient may change ATG12 protein levels, contributing to PD development as a risk factor by interfering with autophagy as well as non-autophagy functions.Copyright © 2017. Published by Elsevier B.V.
Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy
Feb 23, 2017   Journal Of Neurology
Nakatsuji H, Araki A, Hashizume A, Hijikata Y, Yamada S,   . . . . . .   , Funahashi T, Shimomura I, Okano H, Katsuno M, Sobue G
Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy
Feb 23, 2017
Journal Of Neurology
This study aimed to evaluate various metabolic parameters in patients with spinal and bulbar muscular atrophy (SBMA), to investigate the association between those indices and disease severity, and to explore the underlying molecular pathogenesis. We compared the degree of obesity, metabolic parameters, and blood pressure in 55 genetically confirmed SBMA patients against those in 483 age- and sex-matched healthy control. In SBMA patients, we investigated the correlation between these factors and motor functional indices. SBMA patients had lower body mass index, blood glucose, and Hemoglobin A1c, but higher blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR, a marker of insulin resistance), total cholesterol, and adiponectin levels than the control subjects. There were no differences in visceral fat areas, high-density lipoprotein-cholesterol (HDL-C), or triglyceride levels in two groups. Revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) correlated positively with HDL-C, but negatively with HOMA-IR. Through stepwise multiple regression analysis, we identified HOMA-IR as a significant metabolic determinant of ALSFRS-R. In biochemical analysis, we found that decreased expressions of insulin receptors, insulin receptor substrate-1 and insulin receptor-β, in autopsied muscles and fibroblasts of SBMA patients. This study demonstrates that SBMA patients have insulin resistance, which is associated with the disease severity. The expressions of insulin receptors are attenuated in the skeletal muscle of SBMA, providing a possible pathomechanism of metabolic alterations. These findings suggested that insulin resistance is a metabolic index reflecting disease severity and pathogenesis as well as a potential therapeutic target for SBMA.
The Parkinson's Disease-Cognitive Rating Scale (PD-CRS): normative values from 268 healthy Italian individuals
Feb 22, 2017   Neurological Sciences : Official Journal Of The Italian Neurological Society And Of The Italian Society Of Clinical Neurophysiology
Santangelo G, Lagravinese G, Battini V, Chiorri C, Siciliano M, Abbruzzese G, Vitale C, Barone P
The Parkinson's Disease-Cognitive Rating Scale (PD-CRS): normative values from 268 healthy Italian individuals
Feb 22, 2017
Neurological Sciences : Official Journal Of The Italian Neurological Society And Of The Italian Society Of Clinical Neurophysiology
UNASSIGNED: The Parkinson's Disease-Cognitive Rating Scale (PD-CRS) is a cognitive screening battery that includes subtests to assess cortical and subcortical functions. It is a valid screening tool for mild cognitive impairment (MCI) in Parkinson's disease (PD) and is recommended for diagnosing PD-MCI-Level I. Until now, no study has provided population-based norms for the Italian population. The aim of the present study was to collect normative values in a sample of Italian healthy subjects. Two hundred and sixty-eight (125 men) participants of different ages (age range 30-79 years) and educational levels (from primary school to university) underwent the PD-CRS. Regression-based norming was used to explore the influence of demographic variables (age, education level, and gender) on PD-CRS total score, frontal-subcortical and instrumental-cortical sub-scores, and score achieved on each task of the PD-CRS. Multiple linear regression analysis revealed that age and education significantly predicted the total score, the two sub-scores and the score on each task of the PD-CRS. No significant effect of gender was found. From the derived linear equations, a correction grid for raw scores was developed. Inferential cut-off scores, estimated using a non-parametric technique, were 71.25 for PD-CRS total score and 46.25 and 20.17 for frontal-subcortical and instrumental-cortical sub-score, respectively. Since the use of adjusted scores is more informative when they are standardized, we have converted adjusted scores into equivalent scores. The present study provides normative data for the PD-CRS, being useful and recommended by Movement Disorders Society task force to identify PD-MCI-Level I, at several stages of the disease.
Outcomes after diagnosis of mild cognitive impairment in a large autopsy series
Feb 22, 2017   Annals Of Neurology
Abner EL, Kryscio RJ, Schmitt FA, Fardo DW, Moga DC,   . . . . . .   , Woltjer RL, Schneider JA, Cairns NJ, Bennett DA, Nelson PT
Outcomes after diagnosis of mild cognitive impairment in a large autopsy series
Feb 22, 2017
Annals Of Neurology
OBJECTIVE: Determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI). METHODS: Data were drawn from a large autopsy series (N=1,337) of individuals followed longitudinally from normal or MCI status to death, derived from four Alzheimer's Disease (AD) Centers in the United States. RESULTS: Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% died with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical diagnosis of MCI. In terms of non-AD pathologies, both primary age-related tauopathy (p
Eighth International Chorea-Acanthocytosis Symposium: Summary of Workshop Discussion and Action Points
Feb 22, 2017   Tremor And Other Hyperkinetic Movements (New York, N.Y.)
Pappas SS, Bonifacino J, Danek A, Dauer WT, De M,   . . . . . .   , Velayos-Baeza A, Vonk JJ, Walker RH, Weisman LS, Albin RL
Eighth International Chorea-Acanthocytosis Symposium: Summary of Workshop Discussion and Action Points
Feb 22, 2017
Tremor And Other Hyperkinetic Movements (New York, N.Y.)
UNASSIGNED: Chorea-Acanthocytosis (ChAc) is a rare hereditary neurological disorder characterized by abnormal movements, red blood cell pathology, and progressive neurodegeneration. Little is understood of the pathogenesis of ChAc and related disorders (collectively Neuroacanthocytosis). The Eighth International Chorea-Acanthocytosis Symposium was held in May 2016 in Ann Arbor, MI, USA, and focused on molecular mechanisms driving ChAc pathophysiology. Accompanying the meeting, members of the neuroacanthocytosis research community and other invited scientists met in a workshop to discuss the current understanding and next steps needed to better understand ChAc pathogenesis. These discussions identified several broad and critical needs for advancing ChAc research and patient care, and led to the definition of 18 specific action points related to functional and molecular studies, animal models, and clinical research. These action points, described below, represent tractable research goals to pursue for the next several years.
Plasma Cystatin C and High-Density Lipoprotein Are Important Biomarkers of Alzheimer's Disease and Vascular Dementia: A Cross-Sectional Study
Feb 22, 2017   Frontiers In Aging Neuroscience
Wang R, Chen Z, Fu Y, Wei X, Liao J,   . . . . . .   , Weng R, Tan S, McElroy C, Jin K, Wang Q
Plasma Cystatin C and High-Density Lipoprotein Are Important Biomarkers of Alzheimer's Disease and Vascular Dementia: A Cross-Sectional Study
Feb 22, 2017
Frontiers In Aging Neuroscience
HIGHLIGHTS: Plasma Cys C levels were higher in patients with AD/VaD than in healthy subjects.Plasma HDL levels were lower in patients with AD/VaD than in healthy subjects.Plasma Cys C levels were significantly correlated with dementia.The ROC curve for the combination of Cys C and HDL showed potential diagnostic value in distinguishing AD/VaD from healthy subjects.
Feb 22, 2017   Frontiers In Molecular Neuroscience
Cai Y, Sun Z, Jia H, Luo H, Ye X, Wu Q, Xiong Y, Zhang W, Wan J
Feb 22, 2017
Frontiers In Molecular Neuroscience
UNASSIGNED: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. Recent studies employing microRNA-seq and genome-wide sequencing have identified some non-coding RNAs that are influentially involved in AD pathogenesis. Non-coding RNAs can compete with other endogenous RNAs by microRNA response elements (MREs) and manipulate biological processes, such as tumorigenesis. However, only a few non-coding RNAs have been reported in the pathogenesis of AD. In this study, we constructed the first competing endogenous RNA (ceRNA) network leveraging whole transcriptome sequencing and a previously studied microRNA-seq of APPswe/PS1ΔE9 transgenic mice. The underlying mechanisms for the involvement of ceRNA in AD were validated using the Dual Luciferase Reporter Assay, detection of transcription levels by quantitative RT-PCR and translation levels by Western blotting, and morphological examination in primary cultured neurons. In the ceRNA network, four lncRNAs (C030034L19Rik,
Altered enhancer transcription underlies Huntington's disease striatal transcriptional signature
Feb 22, 2017   Scientific Reports
Le Gras S, Keime C, Anthony A, Lotz C, De Longprez L, Brouillet E, Cassel JC, Boutillier AL, Merienne K
Altered enhancer transcription underlies Huntington's disease striatal transcriptional signature
Feb 22, 2017
Scientific Reports
UNASSIGNED: Epigenetic and transcriptional alterations are both implicated in Huntington's disease (HD), a progressive neurodegenerative disease resulting in degeneration of striatal neurons in the brain. However, how impaired epigenetic regulation leads to transcriptional dysregulation in HD is unclear. Here, we investigated enhancer RNAs (eRNAs), a class of long non-coding RNAs transcribed from active enhancers. We found that eRNAs are expressed from many enhancers of mouse striatum and showed that a subset of those eRNAs are deregulated in HD vs control mouse striatum. Enhancer regions producing eRNAs decreased in HD mouse striatum were associated with genes involved in striatal neuron identity. Consistently, they were enriched in striatal super-enhancers. Moreover, decreased eRNA expression in HD mouse striatum correlated with down-regulation of associated genes. Additionally, a significant number of RNA Polymerase II (RNAPII) binding sites were lost within enhancers associated with decreased eRNAs in HD vs control mouse striatum. Together, this indicates that loss of RNAPII at HD mouse enhancers contributes to reduced transcription of eRNAs, resulting in down-regulation of target genes. Thus, our data support the view that eRNA dysregulation in HD striatum is a key mechanism leading to altered transcription of striatal neuron identity genes, through reduced recruitment of RNAPII at super-enhancers.
NMDA receptor subunit and CaMKII changes in rat hippocampus by congenital HCMV infection: a mechanism for learning and memory impairment
Feb 22, 2017   Neuroreport
Wu , Yang L, Bu X, Tang J, Fan X
NMDA receptor subunit and CaMKII changes in rat hippocampus by congenital HCMV infection: a mechanism for learning and memory impairment
Feb 22, 2017
Neuroreport
UNASSIGNED: The aim of this study was to investigate the effects of congenital human cytomegalovirus infection on the expression levels of N-methyl-D-aspartate receptors (NRs) and Ca/calmodulin-dependent protein kinase II (CaMKII) in the hippocampal neurons of neonatal Sprague-Dawley (SD) rats. Pregnant SD rats were divided into an experimental group and a control group (n=10 in each group). Spatial learning and memory of the offspring of SD rats were evaluated using the Morris water-maze test. Pathological studies of hippocampus sections were carried out. The concentration of [Ca] was measured using a dual-wavelength spectrophotometer method. The expression levels of NRs were detected by an immunohistochemical study. Western blot was performed to detect the expression level of CaMKII. In the Morris water-maze test, the rats in the experimental group showed significantly increased escape latency and distance traveled than the control group. Damaged and structural disorders of the dentate granule in the hippocampus were found in the experimental rats. Immunohistochemistry results showed that the expression levels of NR subunits in the hippocampus of the experimental group were significantly decreased. The concentration of [Ca] in the experimental group was significantly increased. In contrast, the level of CaMKII in the experimental group was significantly decreased. The expressions of the NR subunit and CaMKII were decreased in rat hippocampus by human cytomegalovirus congenital infection, which may be associated with the mechanism underlying the impairment of learning and memory function.
The clinical, neuroanatomical, and neuropathologic phenotype of
Feb 23, 2017   Alzheimer's & Dementia (Amsterdam, Netherlands)
Koriath CA, Bocchetta M, Brotherhood E, Woollacott IO, Norsworthy P,   . . . . . .   , Warren JD, Revesz T, Lashley T, Mead S, Rohrer JD
The clinical, neuroanatomical, and neuropathologic phenotype of
Feb 23, 2017
Alzheimer's & Dementia (Amsterdam, Netherlands)
INTRODUCTION: Mutations in the TANK-binding kinase 1 ( METHODS: We performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in the RESULTS: The patient presented at the age of 64 years with an 18-month history of personality change including increased rigidity and obsessiveness, apathy, loss of empathy, and development of a sweet tooth. His mother had developed progressive behavioral and cognitive impairment from the age of 57 years. Neuropsychometry revealed intact cognition at first assessment. Magnetic resonance imaging showed focal right temporal lobe atrophy. Over the next few years his behavioral problems progressed and he developed cognitive impairment, initially with anomia and prosopagnosia. Neurological examination remained normal throughout without any features of motor neurone disease. He died at the age of 72 years and postmortem showed TDP-43 type A pathology but with an unusual novel feature of numerous TAR DNA-binding protein 43 (TDP-43)-positive neuritic structures at the cerebral cortex/subcortical white matter junction. There was also associated argyrophilic grain disease not previously reported in other
On an analogue signal processing circuit in the Nematode C. elegans
Feb 23, 2017   Conference Proceedings : ... Annual International Conference Of The IEEE Engineering In Medicine And Biology Society. IEEE Engineering In Medicine And Biology Society. Annual Conference
Skandari R, Iino Y, Manton JH, Skandari R, Iino Y, Manton JH, Skandari R, Iino Y, Manton JH
On an analogue signal processing circuit in the Nematode C. elegans
Feb 23, 2017
Conference Proceedings : ... Annual International Conference Of The IEEE Engineering In Medicine And Biology Society. IEEE Engineering In Medicine And Biology Society. Annual Conference
UNASSIGNED: In this work we will work on analogue signal processing in the neural circuit of C. elegans which is able to detect the analogue signals from the environment and produce locomotive behaviours which are in accordance with experiments. The signals in C. elegans are processed in a purely analogue procedure, since no action potential has been recorded in its neural activity. We aim to show how signal processing can be executed in analogue domain in a living creature. In order to do that we will model two different behaviours of C. elegans which are generated in the same network of neurons, klinotaxis behaviour and isothermal tracking. We will implement a Genetic Algorithm to find appropriate sets of parameters of the model. Our contribution is to show how relatively straight forward differential equations can lead to relatively complex and different behaviours.
Microglia Function in the Central Nervous System During Health and Neurodegeneration
Feb 22, 2017   Annual Review Of Immunology
Colonna M, Butovsky O
Microglia Function in the Central Nervous System During Health and Neurodegeneration
Feb 22, 2017
Annual Review Of Immunology
UNASSIGNED: Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases. Expected final online publication date for the Annual Review of Immunology Volume 35 is April 26, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-response Behaviors in Model Organisms
Feb 22, 2017   Alcoholism, Clinical And Experimental Research
Adkins AE, Hack LM, Bigdeli TB, Williamson VS, McMichael GO,   . . . . . .   , Bettinger JC, Webb BT, Miles MF, Kendler KS, Riley BP
Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-response Behaviors in Model Organisms
Feb 22, 2017
Alcoholism, Clinical And Experimental Research
BACKGROUND: Alcohol Dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. METHODS: We conducted a genomewide association study in 706 related AD cases and 1748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms to assess the role of orthologous genes in ethanol response behaviors. We tested one primate-specific gene for expression differences in case/control post-mortem brain tissue. RESULTS: We detected significant association in COL6A3 and suggestive association in two previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in C. elegans reduced ethanol sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance. Klf12 expression correlated with locomotor activation following ethanol injection in mice. Loss of function of the RYR3 ortholog reduced ethanol sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer ethanol in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens. CONCLUSIONS: We detect association between AD and COL6A3, KLF12, RYR3 and LOC339975. Despite non-replication of COL6A3, KLF12 and RYR3 signals, orthologs of these genes influence behavioral response to ethanol in model organisms, suggesting potential involvement in human ethanol response and AD liability. The associated LOC339975 allele may influence gene expression in human nucleus accumbens. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry
Feb 22, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Zhu H, Zou G, Wang N, Zhuang M, Xiong W, Huang G
Single-neuron identification of chemical constituents, physiological changes, and metabolism using mass spectrometry
Feb 22, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
UNASSIGNED: The use of single-cell assays has emerged as a cutting-edge technique during the past decade. Although single-cell mass spectrometry (MS) has recently achieved remarkable results, deep biological insights have not yet been obtained, probably because of various technical issues, including the unavoidable use of matrices, the inability to maintain cell viability, low throughput because of sample pretreatment, and the lack of recordings of cell physiological activities from the same cell. In this study, we describe a patch clamp/MS-based platform that enables the sensitive, rapid, and in situ chemical profiling of single living neurons. This approach integrates modified patch clamp technique and modified MS measurements to directly collect and detect nanoliter-scale samples from the cytoplasm of single neurons in mice brain slices. Abundant possible cytoplasmic constituents were detected in a single neuron at a relatively fast rate, and over 50 metabolites were identified in this study. The advantages of direct, rapid, and in situ sampling and analysis enabled us to measure the biological activities of the cytoplasmic constituents in a single neuron, including comparing neuron types by cytoplasmic chemical constituents; observing changes in constituent concentrations as the physiological conditions, such as age, vary; and identifying the metabolic pathways of small molecules.

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