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Peter Bannerman, Fuzheng Guo, Olga Chechneva, Travis Burns, Xiaoqing Zhu, Yan Wang, Bokyung Kim, Naveen K Singhal, Jennifer A McDonough, David Pleasure
Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAAB ]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy...
March 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Kazuyuki Sumi, Kyosuke Uno, Hiroshi Noike, Takenori Tomohiro, Yasumaru Hatanaka, Yoko Furukawa-Hibi, Toshitaka Nabeshima, Yoshiaki Miyamoto, Atsumi Nitta
We have identified SHATI/NAT8L in the brain of mice treated with methamphetamine. Recently, it has been reported that SHATI is N-acetyltransferase 8-like protein (NAT8L) that produces N-acetylaspatate (NAA) from aspartate and acetyl-CoA. We have generated SHATI/NAT8L knockout (Shati-/- ) mouse which demonstrates behavioral deficits that are not rescued by single NAA supplementation, although the reason for which is still not clarified. It is possible that the developmental impairment results from deletion of SHATI/NAT8L in the mouse brain, because NAA is involved in myelination through lipid synthesis in oligodendrocytes...
December 4, 2017: Scientific Reports
Kazuya Toriumi, Junko Tanaka, Takayoshi Mamiya, Tursun Alkam, Hyoung-Chun Kim, Atsumi Nitta, Toshitaka Nabeshima
We previously identified a novel molecule, SHATI/NAT8L, as having an inhibitory effect on methamphetamine dependence. We generated Shati/Nat8l knockout (KO) mice and found that they showed neurochemical changes and behavioral abnormalities related to attention deficit/hyperactivity disorder (AD/HD). In this study, we assessed validities of the Shati/Nat8l KO mice as a new animal model for AD/HD through a behavioral pharmacology approach. We conducted a locomotor activity test in a novel environment, a cliff avoidance test, and an object-based attention assay using Shati/Nat8l KO mice at the ages of 4 and 8 weeks...
February 26, 2018: Behavioural Brain Research
Georg von Jonquieres, Ziggy H T Spencer, Benjamin D Rowlands, Claudia B Klugmann, Andre Bongers, Anne E Harasta, Kristina E Parley, Jennie Cederholm, Orla Teahan, Russell Pickford, Fabien Delerue, Lars M Ittner, Dominik Fröhlich, Catriona A McLean, Anthony S Don, Miriam Schneider, Gary D Housley, Caroline D Rae, Matthias Klugmann
N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation...
January 2018: Acta Neuropathologica
Yoshiaki Miyamoto, Noriyuki Iegaki, Kequan Fu, Yudai Ishikawa, Kazuyuki Sumi, Sota Azuma, Kyosuke Uno, Shin-Ichi Muramatsu, Atsumi Nitta
Background: Several clinical studies have suggested that N-acetylaspartate and N-acetylaspartylglutamate levels in the human brain are associated with various psychiatric disorders, including major depressive disorder. We have previously identified Shati/Nat8l, an N-acetyltransferase, in the brain using an animal model of psychosis. Shati/Nat8l synthesizes N-acetylaspartate from L-aspartate and acetyl-coenzyme A. Further, N-acetylaspartate is converted into N-acetylaspartylglutamate, a neurotransmitter for metabotropic glutamate receptor 3...
December 1, 2017: International Journal of Neuropsychopharmacology
Juliane G Bogner-Strauss
N-acetylaspartate (NAA) is a highly abundant brain metabolite. Aberrant NAA concentrations have been detected in many pathological conditions and although the function of NAA has been extensively investigated in the brain it is still controversial. Only recently, a role of NAA has been reported outside the brain. In brown adipocytes, which show high expression of the NAA-producing and the NAA-cleaving enzyme, the metabolism of NAA has been implicated in lipid synthesis and histone acetylation. Increased expression of N-acetyltransferase 8-like (Nat8l, the gene encoding the NAA synthesizing enzyme) induces de novo lipogenesis and the brown adipocyte phenotype...
2017: Frontiers in Endocrinology
Kyosuke Uno, Toh Miyazaki, Kengo Sodeyama, Yoshiaki Miyamoto, Atsumi Nitta
Shati/Nat8L significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that Shati/Nat8L overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that Shati/Nat8L overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated N-acetylaspartylglutamate following N-acetylaspartate increase due to the overexpression...
2017: PloS One
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...
January 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
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...
January 2017: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
Kyosuke Uno, Yuu Kikuchi, Mina Iwata, Takashi Uehara, Tadasu Matsuoka, Tomiki Sumiyoshi, Yoshinori Okamoto, Hideto Jinno, Tatsuyuki Takada, Yoko Furukawa-Hibi, Toshitaka Nabeshima, Yoshiaki Miyamoto, Atsumi Nitta
The number of patients with schizophrenia has increased over the past decade. Previously, many studies have been performed to establish its diagnostic criteria, prophylactic methods, and effective therapies. In this study, we analyzed whether the ratios of DNA methylation in CpG islands of the Shati/Nat8l is decreased in model mice of schizophrenia-like phenotype using genomic DNA collected from brain regions and peripheral blood, since the mouse model of schizophrenia-like phenotype, mice treated repeatedly with methamphetamine showed increase of Shati/Nat8l mRNA expression in our previous experiment...
2016: PloS One
Daniel Weindl, Thekla Cordes, Nadia Battello, Sean C Sapcariu, Xiangyi Dong, Andre Wegner, Karsten Hiller
BACKGROUND: Metabolism gained increasing interest for the understanding of diseases and to pinpoint therapeutic intervention points. However, classical metabolomics techniques only provide a very static view on metabolism. Metabolic flux analysis methods, on the other hand, are highly targeted and require detailed knowledge on metabolism beforehand. RESULTS: We present a novel workflow to analyze non-targeted metabolome-wide stable isotope labeling data to detect metabolic flux changes in a non-targeted manner...
2016: Cancer & Metabolism
Behrouz Zand, Rebecca A Previs, Niki M Zacharias, Rajesha Rupaimoole, Takashi Mitamura, Archana Sidalaghatta Nagaraja, Michele Guindani, Heather J Dalton, Lifeng Yang, Joelle Baddour, Abhinav Achreja, Wei Hu, Chad V Pecot, Cristina Ivan, Sherry Y Wu, Christopher R McCullough, Kshipra M Gharpure, Einav Shoshan, Sunila Pradeep, Lingegowda S Mangala, Cristian Rodriguez-Aguayo, Ying Wang, Alpa M Nick, Michael A Davies, Guillermo Armaiz-Pena, Jinsong Liu, Susan K Lutgendorf, Keith A Baggerly, Menashe Bar Eli, Gabriel Lopez-Berestein, Deepak Nagrath, Pratip K Bhattacharya, Anil K Sood
BACKGROUND: The clinical and biological effects of metabolic alterations in cancer are not fully understood. METHODS: In high-grade serous ovarian cancer (HGSOC) samples (n = 101), over 170 metabolites were profiled and compared with normal ovarian tissues (n = 15). To determine NAT8L gene expression across different cancer types, we analyzed the RNA expression of cancer types using RNASeqV2 data available from the open access The Cancer Genome Atlas (TCGA) website (http://www...
January 26, 2016: Journal of the National Cancer Institute
ShuYa Huang, Wei Lu, Di Ge, Ning Meng, Ying Li, Le Su, ShangLi Zhang, Yun Zhang, BaoXiang Zhao, JunYing Miao
TGFB2-OT1 (TGFB2 overlapping transcript 1) is a newly discovered long noncoding RNA (lncRNA) derived from the 3'UTR of TGFB2. It can regulate autophagy in vascular endothelial cells (VECs). However, the mechanisms of TGFB2-OT1 action are unclear, and whether it is involved in VECs dysfunction needs investigation. Here, the level of TGFB2-OT1 was markedly increased by lipopolysaccharide and oxidized low-density lipoprotein, 2 VECs inflammation triggers. A chemical small molecule, 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) significantly decreased TGFB2-OT1 levels and inhibited the effect of LPS and oxLDL...
2015: Autophagy
Tzu-Fang Lou, Deepa Sethuraman, Patrick Dospoy, Pallevi Srivastva, Hyun Seok Kim, Joongsoo Kim, Xiaotu Ma, Pei-Hsuan Chen, Kenneth E Huffman, Robin E Frink, Jill E Larsen, Cheryl Lewis, Sang-Won Um, Duk-Hwan Kim, Jung-Mo Ahn, Ralph J DeBerardinis, Michael A White, John D Minna, Hyuntae Yoo
In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA), in cancer cells-undetectable in normal lung epithelium. NAA's cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues...
January 2016: Cancer Prevention Research
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
Kazuya Toriumi, Takayoshi Mamiya, Ziyu Song, Tatsuki Honjo, Hiroyuki Watanabe, Junko Tanaka, Mizuki Kondo, Akihiro Mouri, Hyoung-Chun Kim, Atsumi Nitta, Takeshi Fukushima, Toshitaka Nabeshima
We previously identified a novel molecule "SHATI/NAT8L" that exerts an inhibitory effect on methamphetamine (METH)-induced behavioral deficits. Recently, it has been reported that SHATI might function as an aspartate N-acetyltransferase, which synthesizes N-acetylaspartate (NAA) in vitro. However, whether SHATI actually synthesizes NAA in vivo in the brain is still unclear. In this study, we found that both Shati-deleted mice showed significantly lower NAA levels in all brain areas than wild-type (Shati(+/+)) mice using HPLC and fluorescence detection, suggesting that SHATI regulates NAA content in the brain...
November 2015: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Kazuyuki Sumi, Kyosuke Uno, Shohei Matsumura, Yoshiaki Miyamoto, Yoko Furukawa-Hibi, Shin-Ichi Muramatsu, Toshitaka Nabeshima, Atsumi Nitta
A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens of mice repeatedly treated with methamphetamine (METH). Shati/Nat8l has been reported to inhibit the pharmacological action induced by METH. Shati/Nat8l produces N-acetylaspartate from aspartate and acetyl-CoA. Previously, we reported that overexpression of Shati/Nat8l in nucleus accumbens attenuates the response to METH by N-acetylaspartylglutamate (which is derived from N-acetylaspartate)-mGluR3 signaling in the mice brain. In the present study, to clarify the type of cells that produce Shati/Nat8l, we carried out in-situ hybridization for the detection of Shati/Nat8l mRNA along with immunohistochemical studies using serial sections of mice brain...
September 9, 2015: Neuroreport
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
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
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