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aspartoacylase

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https://www.readbyqxmd.com/read/27913587/suppressing-n-acetyl-l-aspartate-naa-synthesis-prevents-loss-of-neurons-in-a-murine-model-of-canavan-leukodystrophy
#1
Jiho Sohn, Peter Bannerman, Fuzheng Guo, Travis Burns, Laird Miers, Christopher Croteau, Naveen K Singhal, Jennifer A McDonough, David Pleasure
Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-L-aspartate (NAA) to acetate and L-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation...
December 2, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27717881/n-acetylaspartate-supports-the-energetic-demands-of-developmental-myelination-via-oligodendroglial-aspartoacylase
#2
Jeremy S Francis, Ireneusz Wojtas, Vladimir Markov, Steven J Gray, Thomas J McCown, R Jude Samulski, Larissa T Bilaniuk, Dah-Jyuu Wang, Darryl C De Vivo, Christopher G Janson, Paola Leone
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression...
December 2016: Neurobiology of Disease
https://www.readbyqxmd.com/read/27709268/the-neuronal-metabolite-naa-regulates-histone-h3-methylation-in-oligodendrocytes-and-myelin-lipid-composition
#3
N K Singhal, H Huang, S Li, R Clements, J Gadd, A Daniels, E E Kooijman, P Bannerman, T Burns, F Guo, D Pleasure, E Freeman, L Shriver, J McDonough
The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L(-/-)) mice which do not synthesize NAA...
October 5, 2016: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/27394419/oligodendrocytes-do-not-export-naa-derived-aspartate-in-vitro
#4
Ana I Amaral, Mussie Ghezu Hadera, Mark Kotter, Ursula Sonnewald
Oligodendroglial cells are known to de-acetylate the N-acetylaspartate (NAA) synthesized and released by neurons and use it for lipid synthesis. However, the role of NAA regarding their intermediary metabolism remains poorly understood. Two hypotheses were proposed regarding the fate of aspartate after being released by de-acetylation: (1) aspartate is metabolized in the mitochondria of oligodendrocyte lineage cells; (2) aspartate is released to the medium. We report here that aspartoacylase mRNA expression increases when primary rat oligodendrocyte progenitor cells (OPCs) differentiate into mature cells in culture...
July 9, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27089954/modeling-the-complete-catalytic-cycle-of-aspartoacylase
#5
Ekaterina D Kots, Maria G Khrenova, Sofya V Lushchekina, Sergei D Varfolomeev, Bella L Grigorenko, Alexander V Nemukhin
The complete catalytic cycle of aspartoacylase (ASPA), a zinc-dependent enzyme responsible for cleavage of N-acetyl-l-aspartate, is characterized by the methods of molecular modeling. The reaction energy profile connecting the enzyme-substrate (ES) and the enzyme-product (EP) complexes is constructed by the quantum mechanics/molecular mechanics (QM/MM) method assisted by the molecular dynamics (MD) simulations with the QM/MM potentials. Starting from the crystal structure of ASPA complexed with the intermediate analogue, the minimum-energy geometry configurations and the corresponding transition states are located...
May 12, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27045997/n-acetylaspartate-catabolism-determines-cytosolic-acetyl-coa-levels-and-histone-acetylation-in-brown-adipocytes
#6
A Prokesch, H J Pelzmann, A R Pessentheiner, K Huber, C T Madreiter-Sokolowski, A Drougard, M Schittmayer, D Kolb, C Magnes, G Trausinger, W F Graier, R Birner-Gruenberger, J A Pospisilik, J G Bogner-Strauss
Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production. Prior to this work, the presence of NAA has not been described in adipocytes. Here, we show that accumulation of NAA decreases the brown adipocyte phenotype. We increased intracellular NAA concentrations in brown adipocytes via media supplementation or knock-down of aspartoacylase and measured reduced lipolysis, thermogenic gene expression, and oxygen consumption...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27039844/raav-gene-therapy-in-a-canavan-s-disease-mouse-model-reveals-immune-impairments-and-an-extended-pathology-beyond-the-central-nervous-system
#7
Seemin Seher Ahmed, Stefan A Schattgen, Ashley E Frakes, Elif M Sikoglu, Qin Su, Jia Li, Thomas G Hampton, Andrew R Denninger, Daniel A Kirschner, Brian Kaspar, Reuben Matalon, Guangping Gao
Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice...
June 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27026062/involvement-of-aspartoacylase-in-tremor-expression-in-rats
#8
Ai Nishitani, Miyuu Tanaka, Saki Shimizu, Naofumi Kunisawa, Mayuko Yokoe, Yusaku Yoshida, Toshiro Suzuki, Tetsushi Sakuma, Takashi Yamamoto, Mitsuru Kuwamura, Shigeo Takenaka, Yukihiro Ohno, Takashi Kuramoto
Essential tremor (ET) is a common movement disorder with a poorly understood etiology. The TRM/Kyo mutant rat, showing spontaneous tremor, is an animal model of ET. Recently, we demonstrated that tremors in these rats emerge when two mutant loci, a missense mutation in the hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (Hcn1) and the tremor (tm) deletion, are present simultaneously. However, we did not identify which gene within the tm deletion causes tremor expression in TRM/Kyo rats...
July 29, 2016: Experimental Animals
https://www.readbyqxmd.com/read/26992473/a-case-of-canavan-disease-with-microcephaly
#9
Vykuntaraju K Gowda, Maya D Bhat, Varun M Srinivasan, Chandrajit Prasad, Asha Benakappa, Mohammed Faruq
BACKGROUND: Canavan disease is an autosomal recessive disorder with spongy degeneration of white matter of the brain. It presents with developmental delay, visual problems and macrocephaly. PATIENT DESCRIPTION: We report a ten-month old boy with Canavan disease who presented with global developmental delay, seizures, abnormal eye movements and microcephaly. RESULTS: MRI brain revealed diffuse involvement of the supra tentorial white matter, globus pallidi, thalami, dentate nuclei and brainstem with sparing of the corpus callosum...
September 2016: Brain & Development
https://www.readbyqxmd.com/read/26797702/structural-modeling-of-p-v31f-variant-in-the-aspartoacylase-gene
#10
Navaneethakrishnan Krishnamoorthy, Hatem Zayed
Aspartoacylase (ASPA) is an abundant enzyme in the brain, which catalyzes the conversion of N-acetylaspartate into acetate and aspartate, deficiency in its activity leads to degeneration of the white matter of the brain and is a recognized cause of Canavan disease (CD), which affect children. Although genotype-phenotype correlation have been reported for Canavan disease patients, this relationships is still not straightforward. In this communication, we use molecular modeling to address the structural consequences resulting from the missense variant p...
June 2016: Metabolic Brain Disease
https://www.readbyqxmd.com/read/26762640/psa-ncam-positive-neural-progenitors-stably-expressing-bdnf-promote-functional-recovery-in-a-mouse-model-of-spinal-cord-injury
#11
Jennifer Butenschön, Tina Zimmermann, Nikolai Schmarowski, Robert Nitsch, Barbara Fackelmeier, Kevin Friedemann, Konstantin Radyushkin, Jan Baumgart, Beat Lutz, Julia Leschik
BACKGROUND: Neural stem cells for the treatment of spinal cord injury (SCI) are of particular interest for future therapeutic use. However, until now, stem cell therapies are often limited due to the inhibitory environment following the injury. Therefore, in this study, we aimed at testing a combinatorial approach with BDNF (brain-derived neurotrophic factor) overexpressing early neural progenitors derived from mouse embryonic stem cells. BDNF is a neurotrophin, which both facilitates neural differentiation of stem cells and favors regeneration of damaged axons...
January 13, 2016: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/26664442/a-novel-mutation-in-aspartoacylase-gene-canavan-disease
#12
Mahmoudreza Ashrafi, Alireza Tavasoli, Pegah Katibeh, Omid Aryani, Mohammad Vafaee-Shahi
Objective Canavan disease (CD) is a type of vacuolating leukodystrophy with autosomal recessive inheritance. Aspartoacylase deficiency results in decrease of myelin biosynthesis, dysmyelination and brain edema. Although CD is a very common in Ashkenazi Jews patients, several cases have been reported from non-Jewish population. This report is based on a homozygous C.202G>A mutation in the ASPA gene identified from an Iranian patient. To our knowledge, this type of mutation has not been reported in non-Jewish population in the literature...
2015: Iranian Journal of Child Neurology
https://www.readbyqxmd.com/read/26586007/atypical-clinical-and-radiological-course-of-a-patient-with-canavan-disease
#13
Catherine Sarret, Odile Boespflug-Tanguy, Diana Rodriguez
Canavan disease (CD) is a rare metabolic disorder caused by aspartoacylase (ASPA) deficiency. It leads to severe neurological degeneration with spongiform brain degeneration. Accumulation of N-acetylaspartate (NAA) in brain and urine is specific to the disease and guides diagnosis. Magnetic resonance imaging (MRI) usually shows diffuse white matter abnormalities with involvement of the basal ganglia. Mild forms of the disease with a more favorable clinical course and radiological involvement of the basal ganglia without white matter abnormalities have also been reported...
April 2016: Metabolic Brain Disease
https://www.readbyqxmd.com/read/26550943/purification-and-characterization-of-aspartate-n-acetyltransferase-a-critical-enzyme-in-brain-metabolism
#14
Qinzhe Wang, Mojun Zhao, Gwenn G Parungao, Ronald E Viola
Canavan disease (CD) is a neurological disorder caused by an interruption in the metabolism of N-acetylaspartate (NAA). Numerous mutations have been found in the enzyme that hydrolyzes NAA, and the catalytic activity of aspartoacylase is significantly impaired in CD patients. Recent studies have also supported an important role in CD for the enzyme that catalyzes the synthesis of NAA in the brain. However, previous attempts to study this enzyme had not succeeded in obtaining a soluble, stable and active form of this membrane-associated protein...
March 2016: Protein Expression and Purification
https://www.readbyqxmd.com/read/26511242/n-acetylaspartate-synthase-deficiency-corrects-the-myelin-phenotype-in-a-canavan-disease-mouse-model-but-does-not-affect-survival-time
#15
Helena Maier, Lihua Wang-Eckhardt, Dieter Hartmann, Volkmar Gieselmann, Matthias Eckhardt
Canavan disease (CD) is a severe, lethal leukodystrophy caused by deficiency in aspartoacylase (ASPA), which hydrolyzes N-acetylaspartate (NAA). In the brains of CD patients, NAA accumulates to high millimolar concentrations. The pathology of the disease is characterized by loss of oligodendrocytes and spongy myelin degeneration in the CNS. Whether accumulating NAA, absence of NAA-derived acetate, or absence of any unknown functions of the ASPA enzyme is responsible for the pathology of the disease is not fully understood...
October 28, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/26364511/potential-biomarkers-associated-with-diabetic-glomerulopathy-through-proteomics
#16
Yung-Chien Hsu, Chen-Chou Lei, Cheng Ho, Ya-Hsueh Shih, Chun-Liang Lin
Diabetic nephropathy (DN) is characterized by the development of progressive glomerulosclerotic lesions gradually leading to an increasing loss of functioning kidney parenchyma. Relatively little proteomic research of isolated glomeruli of experimental animal models has been done so far. Isolated glomerular proteomics is an innovative tool that potentially detects simultaneous expressions of glomeruli in diabetic pathological contexts. We compared the isolated glomerular profiles of rats with and without diabetes...
2015: Renal Failure
https://www.readbyqxmd.com/read/25766789/transcriptional-regulation-of-n-acetylaspartate-metabolism-in-the-5xfad-model-of-alzheimer-s-disease-evidence-for-neuron-glia-communication-during-energetic-crisis
#17
Samantha Zaroff, Paola Leone, Vladimir Markov, Jeremy S Francis
N-acetylaspartate (NAA) provides a non-invasive clinical index of neuronal metabolic integrity across the entire neurodegenerative spectrum. While NAA function is not comprehensively defined, reductions in the brain are associated with compromised mitochondrial metabolism and are tightly linked to ATP. We have undertaken an analysis of abnormalities in NAA during early stage pathology in the 5xFAD mouse model of familial Alzheimer's disease and show here that dysregulated expression of the gene encoding for the rate-limiting NAA synthetic enzyme (Nat8L) is associated with deficits in mitochondrial oxidative phosphorylation in this model system...
March 2015: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/25712859/ablating-n-acetylaspartate-prevents-leukodystrophy-in-a-canavan-disease-model
#18
Fuzheng Guo, Peter Bannerman, Emily Mills Ko, Laird Miers, Jie Xu, Travis Burns, Shuo Li, Ernest Freeman, Jennifer A McDonough, David Pleasure
Canavan disease is caused by inactivating ASPA (aspartoacylase) mutations that prevent cleavage of N-acetyl-L-aspartate (NAA), resulting in marked elevations in central nervous system (CNS) NAA and progressively worsening leukodystrophy. We now report that ablating NAA synthesis by constitutive genetic disruption of Nat8l (N-acetyltransferase-8 like) permits normal CNS myelination and prevents leukodystrophy in a murine Canavan disease model.
May 2015: Annals of Neurology
https://www.readbyqxmd.com/read/25604619/making-the-white-matter-matters-progress-in-understanding-canavan-s-disease-and-therapeutic-interventions-through-eight-decades
#19
Seemin S Ahmed, Guangping Gao
Canavan's disease (CD) is a fatal autosomal recessive pediatric leukodystrophy in which patients show severe neurodegeneration and typically die by the age of 10, though life expectancy in patients can be highly variable. Currently, there is no effective treatment for CD; however, gene therapy seems to be a feasible approach to combat the disease. Being a monogenic defect, the disease provides an excellent model system to develop gene therapy approaches that can be extended to other monogenic leukodystrophies and neurodegenerative diseases...
2015: JIMD Reports
https://www.readbyqxmd.com/read/25573156/acetate-supplementation-as-a-means-of-inducing-glioblastoma-stem-like-cell-growth-arrest
#20
Patrick M Long, Scott W Tighe, Heather E Driscoll, Karen A Fortner, Mariano S Viapiano, Diane M Jaworski
Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-l-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors...
August 2015: Journal of Cellular Physiology
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