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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...
October 5, 2016: 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...
June 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
K Uno, Y Miyamoto, A Nitta
Many psychiatric disorders are caused by the abnormalities of the dopaminergic neuronal system. A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens (NAc) of mice with methamphetamine (METH) treatment. Previously, we reported that suppression of Shati/Nat8l in the NAc enhanced METH-induced behavioral impairment via dopaminergic neuronal regulation by activation of group II mGluRs. In this study, we investigated the effects of Shati/Nat8l on the action of nicotine. AAV vector containing the entire cDNA sequence of Shati/Nat8l (AAV-Shati/Nat8l vector) or AAV-Mock vector were injected in the NAc...
September 2014: Alcohol and Alcoholism: International Journal of the Medical Council on Alcoholism
Yoshiaki Miyamoto, Eriko Saika, Etsuro Hori, Noriyuki Iegaki, Kazuyuki Sumi, Toshitaka Nabeshima, Shin-ichi Muramatsu, Hisao Nishijo, Kyosuke Uno, Atsumi Nitta
Various molecules are involved in drug addiction induced by drugs of abuse. Therefore, the mechanism of drug addiction is still not clear, and it has been a difficulty in the development of preventive and curative drugs for drug dependence. We tried to identify the molecules associated with drug dependence, and found three molecules including shati/nat81. Recently, it has been demonstrated that the substrate for shati/nat81 is aspaltate and shati/nat8l biosynthesizes N-acetylaspartate, which exists abundantly in the mammalian brain...
August 2013: Nihon Shinkei Seishin Yakurigaku Zasshi, Japanese Journal of Psychopharmacology
Yoshiaki Miyamoto, Yudai Ishikawa, Noriyuki Iegaki, Kazuyuki Sumi, Kequan Fu, Keiji Sato, Yoko Furukawa-Hibi, Shin-Ichi Muramatsu, Toshitaka Nabeshima, Kyosuke Uno, Atsumi Nitta
A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens (NAc) of mice with methamphetamine (METH) treatment. Previously we reported that suppression of Shati/Nat8l enhanced METH-induced behavioral alterations via dopaminergic neuronal regulation. However, the physiological mechanisms of Shati/Nat8l on the dopaminergic system in the brain are unclear. In this study, we injected adeno-associated virus (AAV) vector containing Shati/Nat8l into the NAc or dorsal striatum (dS) of mice, to increase Shati/Nat8l expression...
August 2014: International Journal of Neuropsychopharmacology
Kazuya Toriumi, Mizuki Kondo, Taku Nagai, Ryota Hashimoto, Kazutaka Ohi, Ziyu Song, Junko Tanaka, Akihiro Mouri, Takenao Koseki, Hidenaga Yamamori, Yoko Furukawa-Hibi, Takayoshi Mamiya, Takeshi Fukushima, Masatoshi Takeda, Atsumi Nitta, Kiyofumi Yamada, Toshitaka Nabeshima
In a previous report, we identified a novel molecule, SHATI/NAT8L, having an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference (CPP). SHATI/NAT8L attenuates the METH-induced increase in dopamine overflow in the nucleus accumbens (NAc) by promoting plasmalemmal and vesicular dopamine uptake. However, the biological functions of the protein remain unclear. In this study, we explored NAT8L-binding proteins using pull-down assays and identified a number of components of the adaptor protein (AP)-2 complex, which is a multimeric protein localized to the plasma membrane that functions to internalize cargo during clathrin-mediated endocytosis...
March 2014: International Journal of Neuropsychopharmacology
Ariane R Pessentheiner, Helmut J Pelzmann, Evelyn Walenta, Martina Schweiger, Lukas N Groschner, Wolfgang F Graier, Dagmar Kolb, Kyosuke Uno, Toh Miyazaki, Atsumi Nitta, Dietmar Rieder, Andreas Prokesch, Juliane G Bogner-Strauss
NAT8L (N-acetyltransferase 8-like) catalyzes the formation of N-acetylaspartate (NAA) from acetyl-CoA and aspartate. In the brain, NAA delivers the acetate moiety for synthesis of acetyl-CoA that is further used for fatty acid generation. However, its function in other tissues remained elusive. Here, we show for the first time that Nat8l is highly expressed in adipose tissues and murine and human adipogenic cell lines and is localized in the mitochondria of brown adipocytes. Stable overexpression of Nat8l in immortalized brown adipogenic cells strongly increases glucose incorporation into neutral lipids, accompanied by increased lipolysis, indicating an accelerated lipid turnover...
December 13, 2013: Journal of Biological Chemistry
Kazuya Toriumi, Miki Ikami, Mizuki Kondo, Akihiro Mouri, Takenao Koseki, Daisuke Ibi, Yoko Furukawa-Hibi, Taku Nagai, Takayoshi Mamiya, Atsumi Nitta, Kiyofumi Yamada, Toshitaka Nabeshima
We previously identified a new molecule, "SHATI/NAT8L," which has an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference. Nevertheless, the extent of SHATI localization and its functions are only partially understood. In this study, we used the FLAG-tag method to investigate SHATI localization. We found that SHATI was localized to microtubules when expressed in COS7 cells and cortical primary neurons. This distribution of SHATI was less apparent after cells were treated with colchicine, a tubulin polymerization inhibitor that disrupts the microtubule structure...
December 2013: Journal of Neuroscience Research
Prasanth S Ariyannur, Peethambaran Arun, Erin S Barry, Brian Andrews-Shigaki, Asamoah Bosomtwi, Haiying Tang, Reed Selwyn, Neil E Grunberg, John R Moffett, Aryan M A Namboodiri
N-acetylaspartate (NAA) is recognized as a noninvasive diagnostic neuronal marker for a host of neuropsychiatric disorders using magnetic resonance spectroscopy (MRS). Numerous correlative clinical studies have found significant decreases in NAA levels in specific neuronal systems in an array of neuropsychiatric and substance-abuse disorders. We have recently identified the methamphetamine-induced neuronal protein known as "shati" as the NAA biosynthetic enzyme (aspartate N-acetyltransferase [Asp-NAT]; gene Nat8l)...
July 2013: Journal of Neuroscience Research
Yoko Furukawa-Hibi, Atsumi Nitta, Hidefumi Fukumitsu, Hitomi Somiya, Kazuya Toriumi, Shoei Furukawa, Toshitaka Nabeshima, Kiyofumi Yamada
We previously identified a novel molecule "Shati/Nat8l" from the nucleus accumbens of mice. However, the physiological roles of the SHATI protein are not clear. To investigate the effect of SHATI on the central nervous system and behavior, we studied knockout mice of this protein. We carried out various behavior tests using Shati-knockout mice. Shati-knockout mice did not differ from wild type mice in learning and memory. In the open field test, Shati-knockout mice did not differ from wild-type mice in time of stay in the outer, middle and center areas...
September 27, 2012: Neuroscience Letters
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