Article added to library!
x
Pubchase is a service of protocols.io - free, open access, crowdsourced protocols repository. Explore protocols.
Sign in
Reset password
or connect with
Facebook
By signing in you are agreeing to our
Terms Of Service and Privacy Policy
Neurobiology
Neuroprotective Natural Products for the Treatment of Parkinson's Disease by Targeting the Autophagy-Lysosome Pathway: A Systematic Review
May 15, 2017   Phytotherapy Research : PTR
Wang ZY, Liu JY, Yang CB, Malampati S, Huang YY, Li MX, Li M, Song JX
Neuroprotective Natural Products for the Treatment of Parkinson's Disease by Targeting the Autophagy-Lysosome Pathway: A Systematic Review
May 15, 2017
Phytotherapy Research : PTR
The autophagy-lysosome pathway (ALP) is a primary means by which damaged organelles and long-lived proteins are removed from cells and their components recycled. Impairment of the ALP has been found to be linked to the pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of protein aggregates and loss of dopaminergic neurons in the midbrain. In recent years, some active compounds derived from plants have been found to regulate the ALP and to exert neuroprotective effects in experimental models of PD, raising the possibility that autophagy enhancement may be an effective therapeutic strategy in PD treatment. In this review, we summarize recent findings of natural products that enhance ALP and thereby protect against PD. Research articles were retrieved from PubMed using relevant keywords in combination. Papers related to the topic were identified, and then the reliability of the experiments was assessed in terms of methodology. The results suggest that targeting the ALP with natural products is a promising strategy for PD treatment. However, risk of bias exists in some studies due to the defective methodology. Rigorous experimental design following the guidelines of autophagy assays, molecular target identification and in vivo efficacy evaluation is critical for the development of ALP enhancers for PD treatment in future studies. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.
Representations of Novelty and Familiarity in a Mushroom Body Compartment
May 15, 2017   Cell
Hattori D, Aso Y, Swartz KJ, Rubin GM, Abbott LF, Axel R
Representations of Novelty and Familiarity in a Mushroom Body Compartment
May 15, 2017
Cell
Animals exhibit a behavioral response to novel sensory stimuli about which they have no prior knowledge. We have examined the neural and behavioral correlates of novelty and familiarity in the olfactory system of Drosophila. Novel odors elicit strong activity in output neurons (MBONs) of the α'3 compartment of the mushroom body that is rapidly suppressed upon repeated exposure to the same odor. This transition in neural activity upon familiarization requires odor-evoked activity in the dopaminergic neuron innervating this compartment. Moreover, exposure of a fly to novel odors evokes an alerting response that can also be elicited by optogenetic activation of α'3 MBONs. Silencing these MBONs eliminates the alerting behavior. These data suggest that the α'3 compartment plays a causal role in the behavioral response to novel and familiar stimuli as a consequence of dopamine-mediated plasticity at the Kenyon cell-MBONα'3 synapse. Copyright © 2017 Elsevier Inc. All rights reserved.
Hypericum perforatum extract attenuates behavioral, biochemical, and neurochemical abnormalities in Aluminum chloride-induced Alzheimer's disease rats
May 18, 2017   Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
Cao Z, Wang F, Xiu C, Zhang J, Li Y
Hypericum perforatum extract attenuates behavioral, biochemical, and neurochemical abnormalities in Aluminum chloride-induced Alzheimer's disease rats
May 18, 2017
Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
Alzheimer's disease (AD) is a progressive and ultimately fatal neurodegenerative diseases. Aluminum, a neurotoxic metal, is considered as the pathological hallmark and contributing factor of AD. Hypericum perforatum extract (HPE) is a neuroprotective agent that can prevent neurodegenerative pathologies through antioxidants, anti-inflammatory and regulating neurotransmitter release in animal model of neuropathy. The present study aimed to identify the potential neuroprotective of HPE on AlCl3-induced AD rats. Rats were treated with AlCl3 for 90days to induce behavioral, biochemical, and neurochemical similar to AD. From 31thday, the rats were treated with HPE for 60days. Our results showed HPE improved cognitive function in AlCl3-induced AD rats, and attenuated AlCl3-induced increase in acetylcholinesterase activity and glutamic acid level as well as decreased in noradrenaline and dopamine level. In addition, HPE reversed AlCl3-induced hippocampal pathology including amyloid-beta (Aβ) accumulation (elevated Aβ42 level and amyloid plaques), oxidative stress (increased reactive oxygen species level and thiobarbituric acid reactive substances level, decreased glutathione level and superoxide dismutase activity) and neuroinflammatory (increased mRNA expressions of Interleukin-1β, Interleukin-6, Tumor necrosis factor-α and major histocompatibility complex class II) in hippocampus of rats. Thus, HPE is conferred neuroprotection against AlCl3-induced AD like pathology. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Tau at the Crossroads between Neurotoxicity and Neuroprotection
May 18, 2017   Neuron
DeVos SL, Hyman BT
Tau at the Crossroads between Neurotoxicity and Neuroprotection
May 18, 2017
Neuron
In contrast to the idea that tau phosphorylation is toxic, Ittner et al. (2016) recently showed that specific tau phosphorylation is neuroprotective, phenocopying tau ablation (DeVos et al., 2017), thus highlighting the complex tau biology that underlies neurotoxicity and neuroprotection. Copyright © 2017. Published by Elsevier Inc.
Untangling a Cholinergic Pathway from Wakefulness to Memory
May 18, 2017   Neuron
Gais S, Schönauer M
Untangling a Cholinergic Pathway from Wakefulness to Memory
May 18, 2017
Neuron
Acetylcholine is a major modulator of learning and memory, and its availability varies across the sleep-wake cycle. In this issue of Neuron, Papouin et al. (2017) describe a D-serine-dependent pathway involving astroglia by which the transmitter tunes the hippocampus toward memory encoding during wakefulness. Copyright © 2017. Published by Elsevier Inc.
Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy
May 15, 2017   Nature Neuroscience Add nature.com free-link Cancel
Fletcher EV, Simon CM, Pagiazitis JG, Chalif JI, Vukojicic A, Drobac E, Wang X, Mentis GZ
Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy
May 15, 2017
Nature Neuroscience
Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.
Poor human olfaction is a 19th-century myth
May 12, 2017   Science (New York, N.Y.)
McGann JP
Poor human olfaction is a 19th-century myth
May 12, 2017
Science (New York, N.Y.)
It is commonly believed that humans have a poor sense of smell compared to other mammalian species. However, this idea derives not from empirical studies of human olfaction but from a famous 19th-century anatomist's hypothesis that the evolution of human free will required a reduction in the proportional size of the brain's olfactory bulb. The human olfactory bulb is actually quite large in absolute terms and contains a similar number of neurons to that of other mammals. Moreover, humans have excellent olfactory abilities. We can detect and discriminate an extraordinary range of odors, we are more sensitive than rodents and dogs for some odors, we are capable of tracking odor trails, and our behavioral and affective states are influenced by our sense of smell. Copyright © 2017, American Association for the Advancement of Science.
Characterizing microglia activation: a spatial statistics approach to maximize information extraction
May 09, 2017   Scientific Reports
Davis BM, Salinas-Navarro M, Cordeiro MF, Moons L, Groef L
Characterizing microglia activation: a spatial statistics approach to maximize information extraction
May 09, 2017
Scientific Reports
Microglia play an important role in the pathology of CNS disorders, however, there remains significant uncertainty about the neuroprotective/degenerative role of these cells due to a lack of techniques to adequately assess their complex behaviour in response to injury. Advancing microscopy techniques, transgenic lines and well-characterized molecular markers, have made histological assessment of microglia populations more accessible. However, there is a distinct lack of tools to adequately extract information from these images to fully characterise microglia behaviour. This, combined with growing economic pressures and the ethical need to minimise the use of laboratory animals, led us to develop tools to maximise the amount of information obtained. This study describes a novel approach, combining image analysis with spatial statistical techniques. In addition to monitoring morphological parameters and global changes in microglia density, nearest neighbour distance, and regularity index, we used cluster analyses based on changes in soma size and roundness to yield novel insights into the behaviour of different microglia phenotypes in a murine optic nerve injury model. These methods should be considered a generic tool to quantitatively assess microglia activation, to profile phenotypic changes into microglia subpopulations, and to map spatial distributions in virtually every CNS region and disease state.
Physicochemical properties of dietary phytochemicals can predict their passive absorption in the human small intestine
May 17, 2017   Scientific Reports
Selby-Pham SNB, Miller RB, Howell K, Dunshea F, Bennett LE
Physicochemical properties of dietary phytochemicals can predict their passive absorption in the human small intestine
May 17, 2017
Scientific Reports
A diet high in phytochemical-rich plant foods is associated with reducing the risk of chronic diseases such as cardiovascular and neurodegenerative diseases, obesity, diabetes and cancer. Oxidative stress and inflammation (OSI) is the common component underlying these chronic diseases. Whilst the positive health effects of phytochemicals and their metabolites have been demonstrated to regulate OSI, the timing and absorption for best effect is not well understood. We developed a model to predict the time to achieve maximal plasma concentration (Tmax) of phytochemicals in fruits and vegetables. We used a training dataset containing 67 dietary phytochemicals from 31 clinical studies to develop the model and validated the model using three independent datasets comprising a total of 108 dietary phytochemicals and 98 pharmaceutical compounds. The developed model based on dietary intake forms and the physicochemical properties lipophilicity and molecular mass accurately predicts Tmax of dietary phytochemicals and pharmaceutical compounds over a broad range of chemical classes. This is the first direct model to predict Tmax of dietary phytochemicals in the human body. The model informs the clinical dosing frequency for optimising uptake and sustained presence of dietary phytochemicals in circulation, to maximise their bio-efficacy for positively affect human health and managing OSI in chronic diseases.
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons
May 20, 2017   Scientific Reports
Burk K, Murdoch JD, Freytag S, Koenig M, Bharat V, Markworth R, Burkhardt S, Fischer A, Dean C
EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons
May 20, 2017
Scientific Reports
The sorting of activated receptors into distinct endosomal compartments is essential to activate specific signaling cascades and cellular events including growth and survival. However, the proteins involved in this sorting are not well understood. We discovered a novel role of EndophilinAs in sorting of activated BDNF-TrkB receptors into late endosomal compartments. Mice lacking all three EndophilinAs accumulate Rab7-positive late endosomes. Moreover, EndophilinAs are differentially localized to, co-traffic with, and tubulate, distinct endosomal compartments: In response to BDNF, EndophilinA2 is recruited to both early and late endosomes, EndophilinA3 is recruited to Lamp1-positive late endosomes, and co-trafficks with Rab5 and Rab7 in both the presence and absence of BDNF, while EndophilinA1 colocalizes at lower levels with endosomes. The absence of all three EndophilinAs caused TrkB to accumulate in EEA1 and Rab7-positive endosomes, and impaired BDNF-TrkB-dependent survival signaling cascades. In addition, EndophilinA triple knockout neurons exhibited increased cell death which could not be rescued by exogenous BDNF, in a neurotrophin-dependent survival assay. Thus, EndophilinAs differentially regulate activated receptor sorting via distinct endosomal compartments to promote BDNF-dependent cell survival.
Expression Profiling of mRNAs and Long Non-Coding RNAs in Aged Mouse Olfactory Bulb
May 19, 2017   Scientific Reports
Wang M, Liu W, Jiao J, Li J, Wang C, Zhang L
Expression Profiling of mRNAs and Long Non-Coding RNAs in Aged Mouse Olfactory Bulb
May 19, 2017
Scientific Reports
Age-related decline in olfactory function affects the quality of life in elderly people and also potentially represents an early clinical symptom of neurodegenerative disorder. Olfactory bulb (OB) plays a central role in olfactory information transmitting and signal processing. The mechanisms underlying this impairment remain unclear. In the current study, microarray was used to investigate differentially expressed protein coding genes (PCGs) and long non-coding RNAs (lncRNAs) in OBs from three groups of mice of different ages (2 months-old young adults, 6 months-old mature adults and 20 months-old aged adults), for their potential roles in olfactory impairment. Gene Ontology and pathway analysis results showed that the differentially expressed PCGs in the OBs from aged mice were mainly associated with signal transduction, regulation of gene expression and cellular microenvironment. Similarly, gene set enrichment analysis identified two differentially and inversely expressed lncRNAs (NONMMUT004524 and NONMMUT000384), both of which were significantly associated with neuroactive ligand-receptor interaction pathway in the OBs of aged mice. These findings suggest that a decline of olfactory function in aged mice may be linked to differential expression of specific lncRNAs and their potentially adverse effects on the neuroactive ligand-receptor interaction pathway in the OB.
Age-related penetrance of the C9orf72 repeat expansion
May 19, 2017   Scientific Reports
Murphy NA, Arthur KC, Tienari PJ, Houlden H, Chiò A, Traynor BJ
Age-related penetrance of the C9orf72 repeat expansion
May 19, 2017
Scientific Reports
A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.
Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
May 18, 2017   Scientific Reports
Mirra A, Rossi S, Scaricamazza S, Di Salvio M, Salvatori I, Valle C, Rusmini P, Poletti A, Cestra G, Carrì MT, Cozzolino MO
Functional interaction between FUS and SMN underlies SMA-like splicing changes in wild-type hFUS mice
May 18, 2017
Scientific Reports
Several of the identified genetic factors in Amyotrophic Lateral Sclerosis (ALS) point to dysfunction in RNA processing as a major pathogenic mechanism. However, whether a precise RNA pathway is particularly affected remains unknown. Evidence suggests that FUS, that is mutated in familial ALS, and SMN, the causative factor in Spinal Muscular Atrophy (SMA), cooperate to the same molecular pathway, i.e. regulation of alternative splicing, and that disturbances in SMN-regulated functions, either caused by depletion of SMN protein (as in the case of SMA) or by pathogenic interactions between FUS and SMN (as in the case of ALS) might be a common theme in both diseases. In this work, we followed these leads and tested their pathogenic relevance in vivo. FUS-associated ALS recapitulates, in transgenic mice, crucial molecular features that characterise mouse models of SMA, including defects in snRNPs distribution and in the alternative splicing of genes important for motor neurons. Notably, altering SMN levels by haploinsufficiency or overexpression does not impact the phenotypes of mouse or Drosophila models of FUS-mediated toxicity. Overall, these findings suggest that FUS and SMN functionally interact and that FUS may act downstream of SMN-regulated snRNP assembly in the regulation of alternative splicing and gene expression.
Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension
May 16, 2017   Scientific Reports
Pousada G, Lupo V, Cástro-Sánchez S, Álvarez-Satta M, Sánchez-Monteagudo A, Baloira A, Espinós C, Valverde D
Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension
May 16, 2017
Scientific Reports
Pulmonary arterial hypertension is a progressive disease that causes the obstruction of precapillary pulmonary arteries and a sustained increase in pulmonary vascular resistance. The aim was to analyze functionally the variants found in the BMPR2 gene and to establish a genotype-phenotype correlation. mRNA expression studies were performed using pSPL3 vector, studies of subcellular localization were performed using pEGFP-N1 vector and luciferase assays were performed using pGL3-Basic vector. We have identified 30 variants in the BMPR2 gene in 27 of 55 patients. In 16 patients we detected pathogenic mutations. Minigene assays revealed that 6 variants (synonymous, missense) result in splicing defect. By immunofluorescence assay, we observed that 4 mutations affect the protein localization. Finally, 4 mutations located in the 5'UTR region showed a decreased transcriptional activity in luciferase assays. Genotype-phenotype correlation, revealed that patients with pathogenic mutations have a more severe phenotype (sPaP p = 0.042, 6MWT p = 0.041), a lower age at diagnosis (p = 0.040) and seemed to have worse response to phosphodiesterase-5-inhibitors (p = 0.010). Our study confirms that in vitro expression analysis is a suitable approach in order to investigate the phenotypic consequences of the nucleotide variants, especially in cases where the involved genes have a pattern of expression in tissues of difficult access.
Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines
May 10, 2017   Scientific Reports
Mao X, Li K, Tang B, Luo Y, Ding D,   . . . . . .   , Xia K, Yan X, Jiang H, Lu S, Guo J
Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines
May 10, 2017
Scientific Reports
Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of "Epilepsy", which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C > T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G > A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.
Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons
May 12, 2017   Scientific Reports
Getz AM, Xu F, Visser F, Persson R, Syed NI
Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons
May 12, 2017
Scientific Reports
In the central nervous system (CNS), cholinergic transmission induces synaptic plasticity that is required for learning and memory. However, our understanding of the development and maintenance of cholinergic circuits is limited, as the factors regulating the expression and clustering of neuronal nicotinic acetylcholine receptors (nAChRs) remain poorly defined. Recent studies from our group have implicated calpain-dependent proteolytic fragments of menin, the product of the MEN1 tumor suppressor gene, in coordinating the transcription and synaptic clustering of nAChRs in invertebrate central neurons. Here, we sought to determine whether an analogous cholinergic mechanism underlies menin's synaptogenic function in the vertebrate CNS. Our data from mouse primary hippocampal cultures demonstrate that menin and its calpain-dependent C-terminal fragment (C-menin) regulate the subunit-specific transcription and synaptic clustering of neuronal nAChRs, respectively. MEN1 knockdown decreased nAChR α5 subunit expression, the clustering of α7 subunit-containing nAChRs at glutamatergic presynaptic terminals, and nicotine-induced presynaptic facilitation. Moreover, the number and function of glutamatergic synapses was unaffected by MEN1 knockdown, indicating that the synaptogenic actions of menin are specific to cholinergic regulation. Taken together, our results suggest that the influence of menin on synapse formation and synaptic plasticity occur via modulation of nAChR channel subunit composition and functional clustering.
"TORNADO" - Theranostic One-Step RNA Detector; microfluidic disc for the direct detection of microRNA-134 in plasma and cerebrospinal fluid
May 12, 2017   Scientific Reports
McArdle H, Jimenez-Mateos EM, Raoof R, Carthy E, Boyle D,   . . . . . .   , Kӧrtvelyessy P, Rosenow F, Forster RJ, Henshall DC, Spain E
"TORNADO" - Theranostic One-Step RNA Detector; microfluidic disc for the direct detection of microRNA-134 in plasma and cerebrospinal fluid
May 12, 2017
Scientific Reports
Diagnosis of seizure disorders such as epilepsy currently relies on clinical examination and electroencephalogram recordings and is associated with substantial mis-diagnosis. The miRNA, miR-134 (MIR134 in humans), has been found to be elevated in brain tissue after experimental status epilepticus and in human epilepsy cells and their detection in biofluids may serve as unique biomarkers. miRNAs from unprocessed human plasma and human cerebrospinal fluid samples were used in a novel electrochemical detection based on electrocatalytic platinum nanoparticles inside a centrifugal microfluidic device where the sandwich assay is formed using an event triggered release system, suitable for the rapid point-of-care detection of low abundance biomarkers of disease. The device has the advantage of controlling the rotation speed of the centrifugal device to pump nanoliter volumes of fluid at a set time and manipulate the transfer of liquids within the device. The centrifugal platform improves reaction rates and yields by proposing efficient mixing strategies to overcome diffusion-limited processes and improve mass transport rates, resulting in reduced hybridization times with a limit of detection of 1 pM target concentration. Plasma and cerebrospinal fluid samples (unprocessed) from patients with epilepsy or who experienced status epilepticus were tested and the catalytic response obtained was in range of the calibration plot. This study demonstrates a rapid and simple detection for epilepsy biomarkers in biofluid.
Comorbidity burden of patients with Parkinson's disease and Parkinsonism between 2003 and 2012: A multicentre, nationwide, retrospective study in China
May 11, 2017   Scientific Reports
Wang X, Zeng F, Jin WS, Zhu C, Wang QH,   . . . . . .   , Lian Y, Xu ZQ, Zhou HD, Zhang T, Wang YJ
Comorbidity burden of patients with Parkinson's disease and Parkinsonism between 2003 and 2012: A multicentre, nationwide, retrospective study in China
May 11, 2017
Scientific Reports
Parkinson's disease (PD) and Parkinsonism are common neurodegenerative disorders with continuously increasing prevalence, causing high global burdens. However, data concerning the comorbidity burden of patients with PD or Parkinsonism in China are lacking. To investigate the health condition and comorbidity burden, a total of 3367 PD and 823 Parkinsonism patients were included from seven tertiary hospitals in seven cities across China from 2003 to 2012. Their comorbidity burden was collected and quantified by the Elixhauser Comorbidity Index (ECI) and Charlson Comorbidity Index (CCI). The comorbidity spectra differed between PD and Parkinsonism patients. Compared with PD patients, Parkinsonism patients were older (69.8 ± 11.5 vs. 67.9 ± 11.4, P 
Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
May 11, 2017   Scientific Reports
Bartolome F, Esteras N, Martin-Requero A, Boutoleau-Bretonniere C, Vercelletto M, Gabelle A, Le Ber I, Honda T, Dinkova-Kostova AT, Hardy J, Carro E, Abramov AY
Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates
May 11, 2017
Scientific Reports
Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency.
A data mining approach using cortical thickness for diagnosis and characterization of essential tremor
May 20, 2017   Scientific Reports
Serrano JI, Romero JP, Castillo MDD, Rocon E, Louis ED, Benito-León J
A data mining approach using cortical thickness for diagnosis and characterization of essential tremor
May 20, 2017
Scientific Reports
Essential tremor (ET) is one of the most prevalent movement disorders. Being that it is a common disorder, its diagnosis is considered routine. However, misdiagnoses may occur regularly. Over the past decade, several studies have identified brain morphometric changes in ET, but these changes remain poorly understood. Here, we tested the informativeness of measuring cortical thickness for the purposes of ET diagnosis, applying feature selection and machine learning methods to a study sample of 18 patients with ET and 18 age- and sex-matched healthy control subjects. We found that cortical thickness features alone distinguished the two, ET from controls, with 81% diagnostic accuracy. More specifically, roughness (i.e., the standard deviation of cortical thickness) of the right inferior parietal and right fusiform areas was shown to play a key role in ET characterization. Moreover, these features allowed us to identify subgroups of ET patients as well as healthy subjects at risk for ET. Since treatment of tremors is disease specific, accurate and early diagnosis plays an important role in tremor management. Supporting the clinical diagnosis with novel computer approaches based on the objective evaluation of neuroimage data, like the one presented here, may represent a significant step in this direction.
Investigation of Pain Mechanisms by Calcium Imaging Approaches
May 14, 2017   Neuroscience Bulletin
Anderson M, Zheng Q, Dong X
Investigation of Pain Mechanisms by Calcium Imaging Approaches
May 14, 2017
Neuroscience Bulletin
Due to the complex circuitry and plethora of cell types involved in somatosensation, it is becoming increasingly important to be able to observe cellular activity at the population level. In addition, since cells rely on an intricate variety of extracellular factors, it is important to strive to maintain the physiological environment. Many electrophysiological techniques require the implementation of artificially-produced physiological environments and it can be difficult to assess the activity of many cells simultaneously. Moreover, imaging Ca2+ transients using Ca2+-sensitive dyes often requires in vitro preparations or in vivo injections, which can lead to variable expression levels. With the development of more sensitive genetically-encoded Ca2+ indicators (GECIs) it is now possible to observe changes in Ca2+ transients in large populations of cells at the same time. Recently, groups have used a GECI called GCaMP to address fundamental questions in somatosensation. Researchers can now induce GCaMP expression in the mouse genome using viral or gene knock-in approaches and observe the activity of populations of cells in the pain pathway such as dorsal root ganglia (DRG), spinal neurons, or glia. This approach can be used in vivo and thus maintains the organism's biological integrity. The implementation of GCaMP imaging has led to many advances in our understanding of somatosensation. Here, we review the current findings in pain research using GCaMP imaging as well as discussing potential methodological considerations.
Combination Therapy with Octyl Gallate and Ferulic Acid Improves Cognition and Neurodegeneration in a Transgenic Mouse Model of Alzheimer Disease
May 17, 2017   The Journal Of Biological Chemistry
Mori T, Koyama N, Tan J, Segawa T, Maeda M, Town T
Combination Therapy with Octyl Gallate and Ferulic Acid Improves Cognition and Neurodegeneration in a Transgenic Mouse Model of Alzheimer Disease
May 17, 2017
The Journal Of Biological Chemistry
To date, there is no effective Alzheimer disease (AD) modifying therapy. Nonetheless, combination therapy holds promise, and nutraceuticals (natural dietary compounds with therapeutic properties) and their synthetic derivatives are well-tolerated candidates. We tested whether combination therapy with octyl gallate (OG) and ferulic acid (FA) improves cognition and mitigates AD-like pathology in the PSAPP transgenic mouse model of cerebral amyloidosis. One-year-old mice with established β-amyloid plaques received daily doses of OG and FA alone or in combination for 3 months. PSAPP mice receiving combination therapy had statistically significantly improved cognitive function versus OG or FA single treatment on some (but not all) measures. We also observed statistically significant further reductions in brain parenchymal and cerebral vascular β-amyloid deposits and brain amyloid β-protein abundance in OG plus FA-treated versus singly-treated PSAPP mice. These effects coincided with enhanced nonamyloidogenic amyloid β-protein precursor (APP) cleavage, increased α-secretase activity, and β-secretase inhibition. We detected elevated expression of nonamyloidogenic soluble APP-α and the α-secretase candidate, a disintegrin and metalloproteinase domain-containing protein 10. Correspondingly, amyloidogenic β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 expression levels were reduced. In parallel, the ratio of β-carboxyl-terminal to α-carboxyl-terminal APP fragment was decreased. OG and FA combination therapy strikingly attenuated neuroinflammation, oxidative stress, and synaptotoxicity. Co-treatment afforded additional statistically significant benefit on some, but not all, of these outcome measures. Taken together, these data provide pre-clinical proof-of-concept for AD combination therapy. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Flavin- containing monooxygenases in aging and disease: emerging roles for ancient enzymes
May 18, 2017   The Journal Of Biological Chemistry
Rossner R, Kaeberlein M, Leiser SF
Flavin- containing monooxygenases in aging and disease: emerging roles for ancient enzymes
May 18, 2017
The Journal Of Biological Chemistry
Flavin- containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well- conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Altered learning, memory and social behavior in type 1 taste receptor subunit 3 knockout mice is associated with neuronal dysfunction
May 19, 2017   The Journal Of Biological Chemistry
Martin B, Wang R, Cong WN, Daimon CM, Wu WW,   . . . . . .   , Etienne H, van Gastel J, Azmi A, Janssens J, Maudsley S
Altered learning, memory and social behavior in type 1 taste receptor subunit 3 knockout mice is associated with neuronal dysfunction
May 19, 2017
The Journal Of Biological Chemistry
The type 1 taste receptor member 3 (T1R3) is a G protein-coupled receptor (GPCR) involved in sweet taste perception. Besides the tongue, the T1R3 receptor is highly expressed in brain areas implicated in cognition, including the hippocampus and cortex. As cognitive decline is often preceded by significant metabolic or endocrinological dysfunctions, regulated by the sweet taste perception system, we hypothesized that a disruption of the sweet taste perception in the brain could have a key role in the development of cognitive dysfunction. To assess the importance of the sweet taste receptors in the brain, we conducted transcriptomic and proteomic analyses of cortical and hippocampal tissues isolated from T1R3 knockout (T1R3KO) mice. The effect of an impaired sweet taste perception system on cognition functions were examined by analyzing synaptic integrity and performing animal behavior on T1R3KO mice. While T1R3 knockout (T1R3KO) mice did not present a metabolically-disrupted phenotype, bioinformatic interpretation of the high-dimensionality data indicated a strong neurodegenerative signature associated with significant alterations in pathways involved in neuritogenesis, dendritic growth and synaptogenesis. Furthermore, a significantly reduced dendritic spine density was observed in T1R3KO mice together with alterations in learning and memory functions as well as sociability deficits. Taken together our data suggest that the sweet taste receptor system plays an important neurotrophic role in extra-lingual central nervous tissue which underpins synaptic function, memory acquisition and social behavior. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
A split-luciferase complementation, real-time reporting assay enables monitoring of the disease-associated transmembrane protein TREM2 in live cells
May 11, 2017   The Journal Of Biological Chemistry
Varnum MM, Clayton KA, Yoshii-Kitahara A, Yonemoto G, Koro L, Ikezu S, Ikezu T
A split-luciferase complementation, real-time reporting assay enables monitoring of the disease-associated transmembrane protein TREM2 in live cells
May 11, 2017
The Journal Of Biological Chemistry
Triggering receptor expressed on myeloid cells 2 (TREM2) is a single transmembrane molecule uniquely expressed in microglia. TREM2 mutations are genetically linked to Nasu-Hakola disease and associated with multiple neurodegenerative disorders, including Alzheimer's disease (AD). TREM2 may regulate microglial inflammation and phagocytosis through coupling to the adaptor protein, TYRO protein tyrosine kinase binding protein (TYROBP). However, there is no functional system for monitoring this protein-protein interaction. We developed a luciferase-based modality for real-time monitoring of TREM2/TYROBP coupling in live cells that utilizes split-luciferase complementation technology based on TREM2 and TYROBP fusion to the C- or N-terminal portion of the Renilla luciferase gene. Transient transfection of human embryonic kidney 293 cells with this reporter vector increased luciferase activity upon stimulation with an antiTREM2 antibody, which induces their homodimerization. This was confirmed by ELISAbased analysis of the TREM2-TYROBP interaction. Antibody-mediated TREM2 stimulation enhanced Syk tyrosine kinase activity and uptake of S. aureus in microglial cell line BV-2 in a Syk kinasedependent manner. Interestingly, the TREM2 T66M mutation significantly enhanced luciferase activity without stimulation, indicating constitutive coupling to TYROBP. Finally, flow cytometry analyses indicated significantly lower surface expression of T66M TREM2 variant than wild type or other TREM2 variants. These results demonstrate that our TREM2 reporter vector is a novel tool for monitoring the TREM2-TYROBP interaction in real-time. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

The link you entered does not seem to be valid

Please make sure the link points to nature.com contains a valid shared_access_token

Downloading PDF to your library...

Uploading PDF...

PDF uploading

Delete tag: