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            -Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons

Furuya, Shigeki; Tabata, Toshihide; Mitoma, Junya; Yamada, Kazuyuki; Yamasaki, Miwako; Makino, Asami; Yamamoto, Toshiyuki; Watanabe, Masahiko; Kano, Masanobu; Hirabayashi, Yoshio

doi:10.1073/pnas.200364497

Cited by 182 publications

(146 citation statements)

References 39 publications

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“…[6][7][8][9] As astrocytes normally provide trophic and antioxidant support for neurons, 17,[33][34][35][36] it is possible that Atm À/À astrocytes are oxidatively stressed and unable to provide adequate antioxidant support to Atm À/À neurons, which may lead to oxidative stress in nearby neurons with resultant neuronal degeneration.…”

Section: Atm-deficient Astrocytes Show Signs Of Oxidative Stress and mentioning

confidence: 99%

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

Liu

Stoica

Yan

et al. 2005

Laboratory Investigation

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ATM kinase, the product of the ataxia telangiectasia mutated (Atm) gene, is activated by genomic damage. ATM plays a crucial role in cell growth and development. Here we report that primary astrocytes isolated from ATMdeficient mice grow slowly, become senescent, and die in culture. However, before reaching senescence, these primary Atm À/À astrocytes, like Atm À/À lymphocytes, show increased spontaneous DNA synthesis. These astrocytes also show markers of oxidative stress and endoplasmic reticulum (ER) stress, including increased levels of heat shock proteins (HSP70 and GRP78), malondialdehyde adducts, Cu/Zn superoxide dismutase, procaspase 12 cleavage, and redox-sensitive phosphorylation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In addition, HSP70 and ERK1/2 phosphorylation are upregulated in the cerebella of ATMdeficient mice. This increase in ERK1/2 phosphorylation is seen primarily in cerebellar astrocytes, or Bergmann glia, near degenerating Purkinje cells. ERK1/2 activation and astrogliosis are also found in other parts of the brain, for example, the cortex. We conclude that ATM deficiency induces intrinsic growth defects, oxidative stress, ER stress, and ERKs activation in astrocytes.

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Section: Atm-deficient Astrocytes Show Signs Of Oxidative Stress and mentioning

confidence: 99%

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

Liu

Stoica

Yan

et al. 2005

Laboratory Investigation

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“…Protein samples (20 g) were fractionated by 12.5% SDS-polyacrylamide gel electrophoresis and electroblotted onto polyvinylidene difluoride membranes. Blotted proteins were probed with antiPhgdh (rabbit) antibody (7,8) and monoclonal anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (mouse monoclonal, Chemicon) antibody and were visualized with peroxidase-conjugated secondary antibodies using 3,3Ј-diaminobenzidine as a substrate. Lipids were extracted via the Bligh-Dyer method (15) from freeze-dried whole heads of the d.p.c.…”

Section: Generation Of Phgdhmentioning

confidence: 99%

“…We have recently identified L-serine to be a key mediator of neurotrophic support that is derived from glial cells (6,7). L-Serine is released by glial cells and, in cultured neurons, is an essential component for survival, neuritogenesis, and functional voltage responses (6,7).…”

mentioning

confidence: 99%

“…L-Serine is released by glial cells and, in cultured neurons, is an essential component for survival, neuritogenesis, and functional voltage responses (6,7). Our previous histological studies demonstrated that Phgdh protein is expressed primarily by neuroepithelial stem cells/radial glia in the germinal zone of embryonic brains and later by astrocytes in mature brains; Phgdh protein, on the other hand, is not expressed by postmitotic neurons (7,8). Thus, it seems very likely that diminished capacity to synthesize L-serine due to lack of Phgdh expression may explain why neurons depend strongly on glial cells for their supply of L-serine (9).…”

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confidence: 99%

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Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality

Yoshida

Furuya²,

Osuka³

et al. 2004

Journal of Biological Chemistry

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132

107

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D-3-Phosphoglyceratedehydrogenase (Phgdh; EC 1.1.1.95) is the first committed enzyme of L-serine biosynthesis in the phosphorylated pathway. To determine the physiological importance of Phgdh-dependent L-serine biosynthesis in vivo, we generated Phgdh-deficient mice using targeted gene disruption in embryonic stem cells. The absence of Phgdh led to a drastic reduction of Lserine metabolites such as phosphatidyl-L-serine and sphingolipids. Phgdh null embryos have small bodies with abnormalities in selected tissues and died after days post-coitum 13.5. Striking abnormalities were evident in the central nervous system in which the Phgdh null mutation culminated in hypoplasia of the telencephalon, diencephalon, and mesencephalon; in particular, the olfactory bulbs, ganglionic eminence, and cerebellum appeared as indistinct structures. These observations demonstrate that the Phgdh-dependent phosphorylated pathway is essential for normal embryonic development, especially for brain morphogenesis.

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“…D-Serine and glycine are both potent co-agonists for NMDA-type glutamate receptors (Mothet et al, 2000). Moreover, L-serine and L-alanine themselves exert their effect as neurotrophic compounds, as they support the survival of neurons under serum-and glia-free culture conditions (Furuya et al, 2000). Altered regulation of these small amino acids in the forebrains of FosB(À/À) mice may therefore partly mediate the increased vulnerability of postsynaptic neurons after a neurotoxic dose of METH.…”

Section: Mechanisms Of Fosb-mediated Protection Of Postsynaptic Neuronsmentioning

confidence: 99%

FosB Null Mutant Mice Show Enhanced Methamphetamine Neurotoxicity: Potential Involvement of FosB in Intracellular Feedback Signaling and Astroglial Function

Kuroda

Ornthanalai

Kato

et al. 2009

Neuropsychopharmacol

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Previous studies show that (1) two members of fos family transcription factors, c-Fos and FosB, are induced in frontal brain regions by methamphetamine; (2) null mutation of c-Fos exacerbates methamphetamine-induced neurotoxicity; and (3) null mutation of FosB enhances behavioral responses to cocaine. Here we sought a role of FosB in responses to methamphetamine by studying FosB null mutant (À/À) mice. After a 10 mg/kg methamphetamine injection, FosB(À/À) mice were more prone to self-injury. Concomitantly, the intracellular feedback regulators of Sprouty and Rad-Gem-Kir (RGK) family transcripts had lower expression profiles in the frontoparietal cortex and striatum of the FosB(À/À) mice. Three days after administration of four 10 mg/kg methamphetamine injections, the frontoparietal cortex and striatum of FosB(À/À) mice contained more degenerated neurons as determined by Fluoro-Jade B staining. The abundance of the small neutral amino acids, serine, alanine, and glycine, was lower and/or was poorly induced after methamphetamine administration in the frontoparietal cortex and striatum of FosB(À/À) mice. In addition, methamphetamine-treated FosB(À/À) frontoparietal and piriform cortices showed more extravasation of immunoglobulin, which is indicative of blood-brain barrier dysfunction. Methamphetamine-induced hyperthermia, brain dopamine content, and loss of tyrosine hydroxylase immunoreactivity in the striatum, however, were not different between genotypes. These data indicate that FosB is involved in thermoregulation-independent protective functions against methamphetamine neurotoxicity in postsynaptic neurons. Our findings suggest two possible mechanisms of FosB-mediated neuroprotection: one is induction of negative feedback regulation within postsynaptic neurons through Sprouty and RGK. Another is supporting astroglial function such as maintenance of the blood-brain barrier, and metabolism of serine and glycine, which are important glial modulators of nerve cells.

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l -Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons

Cited by 182 publications

References 39 publications

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality

FosB Null Mutant Mice Show Enhanced Methamphetamine Neurotoxicity: Potential Involvement of FosB in Intracellular Feedback Signaling and Astroglial Function

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