Age-related changes in D-aspartate oxidase promoter methylation control extracellular D-aspartate levels and prevent precocious cell death during brain aging

Autor: Punzo, Daniela, Errico, Francesco, Cristino, Luigia, Sacchi, Silvia, Keller, Simona, Belardo, Carmela, Luongo, Livio, Nuzzo, Tommaso, Imperatore, Roberta, Florio, Ermanno, De Novellis, Vito, Affinito, Ornella, Migliarini, Sara, Maddaloni, Giacomo, Sisalli, Maria Josè, Pasqualetti, Massimo, Pollegioni, Loredano, Maione, Sabatino, Chiariotti, Lorenzo, Usiello, Alessandro
Přispěvatelé: Punzo, D, Errico, Francesco, Cristino, L, Sacchi, S, Keller, S, Belardo, C, Luongo, L, Nuzzo, T, Imperatore, R, Florio, E, De Novellis, V, Affinito, O, Migliarini, S, Maddaloni, G, Sisalli, Mj, Pasqualetti, M, Pollegioni, L, Maione, S, Chiariotti, Lorenzo, Usiello, A., Errico, F, Luongo, Livio, DE NOVELLIS, Vito, Maione, Sabatino, Chiariotti, L, Usiello, Alessandro
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
D-Aspartate Oxidase
D-amino acid
Aging
Messenger
Inbred C57BL
Transgenic
Mice
0302 clinical medicine
Receptors
Enzyme Inhibitors
Promoter Regions
Genetic
Neurons
DNA methylation
Cell Death
General Neuroscience
Neurodegeneration
Dopaminergic
D-Aspartic Acid
Age Factors
Brain
Articles
Embryo
Azacitidine
NMDA receptor
D-amino acids
N-Methyl-D-Aspartate
D-aspartate oxidase
medicine.medical_specialty
Programmed cell death
Substantia nigra
Mice
Transgenic
Biology
Decitabine
Methylation
Receptors
N-Methyl-D-Aspartate
Promoter Regions
03 medical and health sciences
Genetic
Internal medicine
medicine
Extracellular
Animals
RNA
Messenger
Pars compacta
Mammalian
medicine.disease
Newborn
Embryo
Mammalian
Molecular biology
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
Animals
Newborn
RNA
aging
d-amino acids
neurodegeneration
030217 neurology & neurosurgery
Zdroj: The Journal of neuroscience 36 (2016): 3064–3078. doi:10.1523/JNEUROSCI.3881-15.2016
info:cnr-pdr/source/autori:Punzo, Daniela; Punzo, Daniela; Errico, Francesco; Errico, Francesco; Cristino, Luigia; Sacchi, Silvia; Sacchi, Silvia; Keller, Simona; Keller, Simona; Belardo, Carmela; Luongo, Livio; Nuzzo, Tommaso; Nuzzo, Tommaso; Imperatore, Roberta; Florio, Ermanno; Florio, Ermanno; De Novellis, Vito; Affinito, Ornella; Affinito, Ornella; Migliarini, Sara; Maddaloni, Giacomo; Sisalli, Maria Josè; Pasqualetti, Massimo; Pasqualetti, Massimo; Pollegioni, Loredano; Pollegioni, Loredano; Maione, Sabatino; Chiariotti, Lorenzo; Chiariotti, Lorenzo; Usiello, Alessandro; Usiello, Alessandro/titolo:Age-related changes in D-aspartate oxidase promoter methylation control extracellular D-aspartate levels and prevent precocious cell death during brain aging/doi:10.1523%2FJNEUROSCI.3881-15.2016/rivista:The Journal of neuroscience/anno:2016/pagina_da:3064/pagina_a:3078/intervallo_pagine:3064–3078/volume:36
Popis: The endogenous NMDA receptor (NMDAR) agonist d-aspartate occurs transiently in the mammalian brain because it is abundant during embryonic and perinatal phases before drastically decreasing during adulthood. It is well established that postnatal reduction of cerebral d-aspartate levels is due to the concomitant onset of d-aspartate oxidase (DDO) activity, a flavoenzyme that selectively degrades bicarboxylic d-amino acids. In the present work, we show that d-aspartate content in the mouse brain drastically decreases after birth, whereas Ddo mRNA levels concomitantly increase. Interestingly, postnatal Ddo gene expression is paralleled by progressive demethylation within its putative promoter region. Consistent with an epigenetic control on Ddo expression, treatment with the DNA-demethylating agent, azacitidine, causes increased mRNA levels in embryonic cortical neurons. To indirectly evaluate the effect of a putative persistent Ddo gene hypermethylation in the brain, we used Ddo knock-out mice (Ddo(-/-)), which show constitutively suppressed Ddo expression. In these mice, we found for the first time substantially increased extracellular content of d-aspartate in the brain. In line with detrimental effects produced by NMDAR overstimulation, persistent elevation of d-aspartate levels in Ddo(-/-) brains is associated with appearance of dystrophic microglia, precocious caspase-3 activation, and cell death in cortical pyramidal neurons and dopaminergic neurons of the substantia nigra pars compacta. This evidence, along with the early accumulation of lipufuscin granules in Ddo(-/-) brains, highlights an unexpected importance of Ddo demethylation in preventing neurodegenerative processes produced by nonphysiological extracellular levels of free d-aspartate. SIGNIFICANCE STATEMENT: The enzyme d-aspartate oxidase (DDO) catalyzes the degradation of the NMDA receptor agonist, d-aspartate. In the brain, DDO is expressed only during postnatal life, thus reducing the embryonic storage of d-aspartate and keeping this d-amino acid at low levels during adulthood. Although the presence of DDO in mammals is long established, its biological role in the brain and the mechanism regulating its expression are still unclear. Here, we found that Ddo promoter demethylation enables the postnatal expression of Ddo. Moreover, persistent suppression of Ddo expression leads to persistent spillover of extracellular d-aspartate and produces precocious cell death in the mouse brain, thus suggesting a key role for DDO in preventing early neurodegeneration triggered by excessive NMDA receptor stimulation. The endogenous NMDA receptor (NMDAR) agonist D-aspartate occurs transiently in the mammalian brain because it is abundant during embryonic and perinatal phases before drastically decreasing during adulthood. It is well established that postnatal reduction of cerebral D-aspartate levels is due to the concomitant onset of D-aspartate oxidase (DDO) activity, a flavoenzyme that selectively degrades bicarboxylic D-amino acids. In the present work, we show that D-aspartate content in the mouse brain drastically decreases after birth, whereas Ddo mRNA levels concomitantly increase. Interestingly, postnatal Ddo gene expression is paralleled by progressive demethylation within its putative promoter region. Consistent with an epigenetic control on Ddo expression, treatment with the DNA-demethylating agent, azacitidine, causes increased mRNA levels in embryonic cortical neurons. To indirectly evaluate the effect of a putative persistent Ddo gene hypermethylation in the brain, we used Ddo knock-out mice (Ddo(-/-)), which show constitutively suppressed Ddo expression. In these mice, we found for the first time substantially increased extracellular content of D-aspartate in the brain. In line with detrimental effects produced by NMDAR overstimulation, persistent elevation of D-aspartate levels in Ddo(-/-) brains is associated with appearance of dystrophic microglia, precocious caspase-3 activation, and cell death in cortical pyramidal neurons and dopaminergic neurons of the substantia nigra pars compacta. This evidence, along with the early accumulation of lipufuscin granules in Ddo(-/-) brains, highlights an unexpected importance of Ddo demethylation in preventing neurodegenerative processes produced by nonphysiological extracellular levels of free D-aspartate.
Databáze: OpenAIRE
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