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1.
Neurobiol Dis ; 192: 106413, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38253208

RESUMEN

We recently described increased D- and L-serine concentrations in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, the post-mortem caudate-putamen of human Parkinson's disease (PD) brains and the cerebrospinal fluid (CSF) of de novo living PD patients. However, data regarding blood D- and L-serine levels in PD are scarce. Here, we investigated whether the serum profile of D- and L-serine, as well as the other glutamate N-methyl-D-aspartate ionotropic receptor (NMDAR)-related amino acids, (i) differs between PD patients and healthy controls (HC) and (ii) correlates with clinical-demographic features and levodopa equivalent daily dose (LEDD) in PD. Eighty-three consecutive PD patients and forty-one HC were enrolled. PD cohort underwent an extensive clinical characterization. Serum levels of D- and L-serine, L-glutamate, L-glutamine, L-aspartate, L-asparagine and glycine were determined using High Performance Liquid Chromatography. In age- and sex-adjusted analyses, no differences emerged in the serum levels of D-serine, L-serine and other NMDAR-related amino acids between PD and HC. However, we found that D-serine and D-/Total serine ratio positively correlated with age in PD but not in HC, and also with PD age at onset. Moreover, we found that higher LEDD correlated with lower levels of D-serine and the other excitatory amino acids. Following these results, the addition of LEDD as covariate in the analyses disclosed a selective significant increase of D-serine in PD compared to HC (Δ ≈ 38%). Overall, these findings suggest that serum D-serine and D-/Total serine may represent a valuable biochemical signature of PD.


Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Serina/metabolismo , Dopamina/metabolismo , Levodopa/uso terapéutico , Aminoácidos , Ácido Glutámico , Envejecimiento
2.
Int J Mol Sci ; 25(12)2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38928178

RESUMEN

Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain-including those involving serotonin and dopamine-exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.


Asunto(s)
Ritmo Circadiano , Dopamina , Ratones Noqueados , Serotonina , Triptófano Hidroxilasa , Tirosina 3-Monooxigenasa , Área Tegmental Ventral , Animales , Serotonina/metabolismo , Ratones , Ritmo Circadiano/fisiología , Dopamina/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Tirosina 3-Monooxigenasa/genética , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismo , Triptófano Hidroxilasa/deficiencia , Área Tegmental Ventral/metabolismo , Colecistoquinina/metabolismo , Colecistoquinina/genética , Neuronas Dopaminérgicas/metabolismo , Masculino , Sustancia Negra/metabolismo , Ratones Endogámicos C57BL , Trastorno Bipolar/metabolismo , Trastorno Bipolar/genética
3.
J Neurochem ; 166(3): 534-546, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37332201

RESUMEN

The neuroinflammatory process characterizing multiple sclerosis (MS) is associated with changes in excitatory synaptic transmission and altered central concentrations of the primary excitatory amino acid, L-glutamate (L-Glu). Recent findings report that cerebrospinal fluid (CSF) levels of L-Glu positively correlate with pro-inflammatory cytokines in MS patients. However, to date, there is no evidence about the relationship between the other primary excitatory amino acid, L-aspartate (L-Asp), its derivative D-enantiomer, D-aspartate, and the levels of pro-inflammatory and anti-inflammatory cytokines in the CSF of MS. In the present study, we measured by HPLC the levels of these amino acids in the cortex, hippocampus, cerebellum, and spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE). Interestingly, in support of glutamatergic neurotransmission abnormalities in neuroinflammatory conditions, we showed reduced L-Asp levels in the cortex and spinal cord of EAE mice and increased D-aspartate/total aspartate ratio within the cerebellum and spinal cord of these animals. Additionally, we found significantly decreased CSF levels of L-Asp in both relapsing-remitting (n = 157) MS (RR-MS) and secondary progressive/primary progressive (n = 22) (SP/PP-MS) patients, compared to control subjects with other neurological diseases (n = 40). Importantly, in RR-MS patients, L-Asp levels were correlated with the CSF concentrations of the inflammatory biomarkers G-CSF, IL-1ra, MIP-1ß, and Eotaxin, indicating that the central content of this excitatory amino acid, as previously reported for L-Glu, reflects a neuroinflammatory environment in MS. In keeping with this, we revealed that CSF L-Asp levels were positively correlated with those of L-Glu, highlighting the convergent variation of these two excitatory amino acids under inflammatory synaptopathy occurring in MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratones , Animales , Encefalomielitis Autoinmune Experimental/metabolismo , Esclerosis Múltiple/metabolismo , Ácido Aspártico/líquido cefalorraquídeo , Ácido D-Aspártico/metabolismo , Médula Espinal/metabolismo , Encéfalo/metabolismo , Transmisión Sináptica , Aminoácidos Excitadores/metabolismo , Ácido Glutámico/metabolismo , Citocinas/metabolismo
4.
Neurobiol Dis ; 184: 106226, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37451474

RESUMEN

Loss of dopaminergic midbrain neurons perturbs l-serine and d-serine homeostasis in the post-mortem caudate putamen (CPu) of Parkinson's disease (PD) patients. However, it is unclear whether the severity of dopaminergic nigrostriatal degeneration plays a role in deregulating serine enantiomers' metabolism. Here, through high-performance liquid chromatography (HPLC), we measured the levels of these amino acids in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and MPTP-plus-probenecid (MPTPp)-treated mice to determine whether and how dopaminergic midbrain degeneration affects the levels of serine enantiomers in various basal ganglia subregions. In addition, in the same brain regions, we measured the levels of key neuroactive amino acids modulating glutamatergic neurotransmission, including l-glutamate, glycine, l-aspartate, d-aspartate, and their precursors l-glutamine, l-asparagine. In monkeys, MPTP treatment produced severe denervation of nigrostriatal dopaminergic fibers (⁓75%) and increased the levels of serine enantiomers in the rostral putamen (rPut), but not in the subthalamic nucleus, and the lateral and medial portion of the globus pallidus. Moreover, this neurotoxin significantly reduced the protein expression of the astrocytic serine transporter ASCT1 and the glycolytic enzyme GAPDH in the rPut of monkeys. Conversely, concentrations of d-serine and l-serine, as well as ASCT1 and GAPDH expression were unaffected in the striatum of MPTPp-treated mice, which showed only mild dopaminergic degeneration (⁓30%). These findings unveil a link between the severity of dopaminergic nigrostriatal degeneration and striatal serine enantiomers concentration, ASCT1 and GAPDH expression. We hypothesize that the up-regulation of d-serine and l-serine levels occurs as a secondary response within a homeostatic loop to support the metabolic and neurotransmission demands imposed by the degeneration of dopaminergic neurons.


Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Serina , Ratones , Animales , Serina/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Dopamina/metabolismo , Cuerpo Estriado/metabolismo , Mesencéfalo/metabolismo , Aminoácidos/metabolismo , Putamen/metabolismo , Homeostasis
5.
Neurobiol Dis ; 184: 106203, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37336364

RESUMEN

L-serine generated in astrocytes plays a pivotal role in modulating essential neurometabolic processes, while its enantiomer, D-serine, specifically regulates NMDA receptor (NMDAR) signalling. Despite their physiological relevance in modulating cerebral activity, serine enantiomers metabolism in Parkinson's disease (PD) remains elusive. Using High-Performance Liquid Chromatography (HPLC), we measured D- and L-serine levels along with other amino acids known to modulate NMDAR function, such as L-glutamate, L-aspartate, D-aspartate, and glycine, in the post-mortem caudate putamen (CPu) and superior frontal gyrus (SFG) of PD patients. Moreover, we examined these amino acids in the cerebrospinal fluid (CSF) of de novo living PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients versus subjects with other neurological disorders (OND), used as control. We found higher D-serine and L-serine levels in the CPu of PD patients but not in the SFG, a cerebral region that, in contrast to the CPu, is not innervated by nigral dopaminergic terminals. We also highlighted a significant elevation of both serine enantiomers in the CSF samples from PD but not in those of AD and ALS patients, compared with control subjects. By contrast, none or only minor changes were found in the amount of other NMDAR modulating amino acids. Our findings identify D-serine and L-serine level upregulation as a biochemical signature associated with nigrostriatal dopaminergic degeneration in PD.


Asunto(s)
Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Serina/metabolismo , Putamen/metabolismo , Enfermedad de Alzheimer/metabolismo , Aminoácidos , Receptores de N-Metil-D-Aspartato/metabolismo , N-Metilaspartato , Homeostasis
6.
Int J Mol Sci ; 23(3)2022 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-35163460

RESUMEN

Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (CAP2), the sheddase a disintegrin and metalloproteinase 10 (ADAM10), and the synapse-associated protein 97 (SAP97). Our analysis of the SCZ post-mortem brain indicated increased DLG1 mRNA in DLPFC and decreased CAP2 mRNA in the hippocampus of SCZ patients, compared to non-psychiatric control subjects, while the ADAM10 transcript was unaffected. Conversely, no differences in CAP2, SAP97, and ADAM10 protein levels were detected between SCZ and control individuals in both brain regions. To assess whether DLG1 and CAP2 transcript alterations were selective for SCZ, we also measured their expression in the superior frontal gyrus of patients affected by neurodegenerative disorders, like Parkinson's and Alzheimer's disease. Interestingly, also in Parkinson's disease patients, we found a selective reduction of CAP2 mRNA levels relative to controls but unaltered protein levels. Taken together, we reported for the first time altered CAP2 expression in the brain of patients with psychiatric and neurological disorders, thus suggesting that aberrant expression of this gene may contribute to synaptic dysfunction in these neuropathologies.


Asunto(s)
Proteína ADAM10/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Homólogo 1 de la Proteína Discs Large/genética , Proteínas de la Membrana/genética , Enfermedad de Parkinson/genética , Esquizofrenia/genética , Proteína ADAM10/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Autopsia , Estudios de Casos y Controles , Homólogo 1 de la Proteína Discs Large/metabolismo , Corteza Prefontal Dorsolateral/metabolismo , Femenino , Regulación de la Expresión Génica , Hipocampo/metabolismo , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Esquizofrenia/metabolismo
7.
J Proteome Res ; 20(1): 727-739, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33274941

RESUMEN

d-Amino acids were believed to occur only in bacteria and invertebrates. Today, it is well known that d-amino acids are also present in mammalian tissues in a considerable amount. In particular, high levels of free d-serine (d-Ser) and d-aspartate (d-Asp) are found in the brain. While the functions of d-Ser are well known, many questions remain unanswered regarding the role of d-Asp in the central nervous system. d-Asp is very abundant at the embryonic stage, while it strongly decreases after birth because of the expression of d-aspartate oxidase (Ddo) enzyme, which catalyzes the oxidation of this d-amino acid into oxaloacetate, ammonium, and hydrogen peroxide. Pharmacologically, d-Asp acts as an endogenous agonist of N-methyl d-aspartate and mGlu5 receptors, which are known to control fundamental brain processes, including brain development, synaptic plasticity, and cognition. In this work, we studied a recently generated knockin mouse model (R26ddo/ddo), which was designed to express DDO beginning at the zygotic stage. This strategy enables d-Asp to be almost eliminated in both prenatal and postnatal lives. To understand which biochemical pathways are affected by depletion of d-Asp, in this study, we carried out a metabolomic and lipidomic study of ddo knockin brains at different stages of embryonic and postnatal development, combining nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) techniques. Our study shows that d-Asp deficiency in the brain influences amino acid pathways such as threonine, glycine, alanine, valine, and glutamate. Interestingly, d-Asp is also correlated with metabolites involved in brain development and functions such as choline, creatine, phosphocholine (PCho), glycerophosphocholine (GPCho), sphingolipids, and glycerophospholipids, as well as metabolites involved in brain energy metabolism, such as GPCho, glucose, and lactate.


Asunto(s)
Ácido Aspártico , Ácido D-Aspártico , Aminoácidos , Animales , Encéfalo/metabolismo , Ácido D-Aspártico/metabolismo , Metabolismo Energético , Femenino , Ratones , Embarazo , Receptores de N-Metil-D-Aspartato/metabolismo
8.
J Neurochem ; 159(5): 857-866, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34547109

RESUMEN

Excessive extracellular concentrations of L-glutamate (L-Glu) can be neurotoxic and contribute to neurodegenerative processes in multiple sclerosis (MS). The association between cerebrospinal fluid (CSF) L-Glu levels, clinical features, and inflammatory biomarkers in patients with MS remains unclear. In 179 MS patients (relapsing remitting, RR, N = 157; secondary progressive/primary progressive, SP/PP, N = 22), CSF levels of L-Glu at diagnosis were determined and compared with those obtained in a group of 40 patients with non-inflammatory/non-degenerative disorders. Disability at the time of diagnosis, and after 1 year follow-up, was assessed using the Expanded Disability Status Scale (EDSS). CSF concentrations of lactate and of a large set of pro-inflammatory and anti-inflammatory molecules were explored. CSF levels of L-Glu were slightly reduced in MS patients compared to controls. In RR-MS patients, L-Glu levels correlated with EDSS after 1 year follow-up. Moreover, in MS patients, significant correlations were found between L-Glu and both CSF levels of lactate and the inflammatory molecules interleukin (IL)-2, IL-6, and IL-1 receptor antagonist. Altered expression of L-Glu is associated with disability progression, oxidative stress, and inflammation. These findings identify CSF L-Glu as a candidate neurochemical marker of inflammatory neurodegeneration in MS.


Asunto(s)
Ácido Glutámico/líquido cefalorraquídeo , Mediadores de Inflamación/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Adulto , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico por imagen , Estrés Oxidativo/fisiología
9.
Neurobiol Dis ; 158: 105448, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34280523

RESUMEN

INTRODUCTION: Plasticity at corticostriatal synapses is a key substrate for a variety of brain functions - including motor control, learning and reward processing - and is often disrupted in disease conditions. Despite intense research pointing toward a dynamic interplay between glutamate, dopamine (DA), and serotonin (5-HT) neurotransmission, their precise circuit and synaptic mechanisms regulating their role in striatal plasticity are still unclear. Here, we analyze the role of serotonergic raphe-striatal innervation in the regulation of DA-dependent corticostriatal plasticity. METHODS: Mice (males and females, 2-6 months of age) were housed in standard plexiglass cages at constant temperature (22 ± 1°C) and maintained on a 12/12h light/dark cycle with food and demineralized water ad libitum. In the present study, we used a knock-in mouse line in which the green fluorescent protein reporter gene (GFP) replaced the I Tph2 exon (Tph2GFP mice), allowing selective expression of GFP in the whole 5-HT system, highlighting both somata and neuritis of serotonergic neurons. Heterozygous, Tph2+/GFP, mice were intercrossed to obtain experimental cohorts, which included Wild-type (Tph2+/+), Heterozygous (Tph2+/GFP), and Mutant serotonin-depleted (Tph2GFP/GFP) animals. RESULTS: Using male and female mice, carrying on different Tph2 gene dosages, we show that Tph2 gene modulation results in sex-specific corticostriatal abnormalities, encompassing the abnormal amplitude of spontaneous glutamatergic transmission and the loss of Long Term Potentiation (LTP) in Tph2GFP/GFP mice of both sexes, while this form of plasticity is normally expressed in control mice (Tph2+/+). Once LTP is induced, only the Tph2+/GFP female mice present a loss of synaptic depotentiation. CONCLUSION: We showed a relevant role of the interaction between dopaminergic and serotonergic systems in controlling striatal synaptic plasticity. Overall, our data unveil that 5-HT plays a primary role in regulating DA-dependent corticostriatal plasticity in a sex-related manner and propose altered 5-HT levels as a critical determinant of disease-associated plasticity defects.


Asunto(s)
Neostriado/fisiología , Plasticidad Neuronal/fisiología , Serotonina/fisiología , Sinapsis/fisiología , Animales , Animales Modificados Genéticamente , Fenómenos Electrofisiológicos , Femenino , Ácido Glutámico/fisiología , Potenciación a Largo Plazo , Masculino , Ratones , Fibras Nerviosas , Enfermedad de Parkinson Secundaria/fisiopatología , Caracteres Sexuales , Transmisión Sináptica/fisiología , Triptófano Hidroxilasa/metabolismo
10.
Amino Acids ; 53(3): 435-449, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33616735

RESUMEN

Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer's disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between serum L-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Glicina/metabolismo , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Biomarcadores/análisis , Biomarcadores/metabolismo , Cromatografía Líquida de Alta Presión , Femenino , Ácido Glutámico/análisis , Glutamina/análisis , Glicina/análisis , Humanos , Masculino , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología
11.
Int J Mol Sci ; 22(10)2021 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-34070217

RESUMEN

Rhes is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. Rhes mRNA is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D2 and adenosine A2A receptors. Rhes transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain. In line with Rhes-dependent regulation of dopaminergic transmission, data showed that lack of Rhes enhanced cocaine- and amphetamine-induced motor stimulation in mice. Previous studies showed that pharmacological depletion of dopamine significantly reduces Rhes mRNA levels in rodents, non-human primates and Parkinson's disease (PD) patients, suggesting a link between dopaminergic innervation and physiological Rhes mRNA expression. Rhes protein binds to and activates striatal mTORC1, and modulates L-DOPA-induced dyskinesia in PD rodent models. Finally, Rhes is involved in the survival of mouse midbrain dopaminergic neurons of SNc, thus pointing towards a Rhes-dependent modulation of autophagy and mitophagy processes, and encouraging further investigations about mechanisms underlying dysfunctions of the nigrostriatal system.


Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Proteínas de Unión al GTP/metabolismo , Enfermedad de Parkinson/metabolismo , Animales , Autofagia , Encéfalo/metabolismo , Encéfalo/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Unión al GTP/deficiencia , Proteínas de Unión al GTP/genética , Regulación de la Expresión Génica , Humanos , Levodopa/metabolismo , Ratones , Ratones Noqueados , Mitofagia , Modelos Neurológicos , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Transmisión Sináptica
12.
Mult Scler ; 26(3): 304-311, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-30730244

RESUMEN

BACKGROUND: Synaptic plasticity reserve correlates with clinical recovery after a relapse in relapsing-remitting forms of multiple sclerosis (MS) and is significantly compromised in patients with progressive forms of MS. These findings suggest that progression of disability in MS is linked to reduced synaptic plasticity reserve. D-Aspartate, an endogenous aminoacid approved for the use in humans as a dietary supplement, enhances synaptic plasticity in mice. OBJECTIVE: To test whether D-Aspartate oral intake increases synaptic plasticity reserve in progressive MS patients. METHODS: A total of 31 patients affected by a progressive form of MS received either single oral daily doses of D-Aspartate 2660 mg or placebo for 4 weeks. Synaptic plasticity reserve and trans-synaptic cortical excitability were measured through transcranial magnetic stimulation (TMS) protocols before and after D-Aspartate. RESULTS: Both TMS-induced long-term potentiation (LTP), intracortical facilitation (ICF) and short-interval ICF increased after 2 and 4 weeks of D-Aspartate but not after placebo, suggesting an enhancement of synaptic plasticity reserve and increased trans-synaptic glutamatergic transmission. CONCLUSION: Daily oral D-Aspartate 2660 mg for 4 weeks enhances synaptic plasticity reserve in patients with progressive MS, opening the path to further studies assessing its clinical effects on disability progression.


Asunto(s)
Ácido D-Aspártico/farmacología , Potenciales Evocados Motores/efectos de los fármacos , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Plasticidad Neuronal/efectos de los fármacos , Adulto , Ácido D-Aspártico/administración & dosificación , Femenino , Humanos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Persona de Mediana Edad , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Estimulación Magnética Transcraneal
13.
Amino Acids ; 52(4): 597-617, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32185508

RESUMEN

The free D-amino acid, D-aspartate, is abundant in the embryonic brain but significantly decreases after birth. Besides its intracellular occurrence, D-aspartate is also present at extracellular level and acts as an endogenous agonist for NMDA and mGlu5 receptors. These findings suggest that D-aspartate is a candidate signaling molecule involved in neural development, influencing brain morphology and behaviors at adulthood. To address this issue, we generated a knockin mouse model in which the enzyme regulating D-aspartate catabolism, D-aspartate oxidase (DDO), is expressed starting from the zygotic stage, to enable the removal of D-aspartate in prenatal and postnatal life. In line with our strategy, we found a severe depletion of cerebral D-aspartate levels (up to 95%), since the early stages of mouse prenatal life. Despite the loss of D-aspartate content, Ddo knockin mice are viable, fertile, and show normal gross brain morphology at adulthood. Interestingly, early D-aspartate depletion is associated with a selective increase in the number of parvalbumin-positive interneurons in the prefrontal cortex and also with improved memory performance in Ddo knockin mice. In conclusion, the present data indicate for the first time a biological significance of precocious D-aspartate in regulating mouse brain formation and function at adulthood.


Asunto(s)
Encéfalo/embriología , D-Aspartato Oxidasa/metabolismo , Ácido D-Aspártico/deficiencia , Animales , Encéfalo/metabolismo , Cognición , D-Aspartato Oxidasa/genética , Técnicas de Sustitución del Gen , Ácido Glutámico/análisis , Masculino , Ratones , Prueba del Laberinto Acuático de Morris , Prueba de Campo Abierto , Corteza Prefrontal/embriología , Corteza Prefrontal/metabolismo , Serina/análisis
14.
Int J Mol Sci ; 21(22)2020 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-33218144

RESUMEN

The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.


Asunto(s)
Encéfalo/metabolismo , Ácido D-Aspártico/metabolismo , Sistemas Neurosecretores/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , D-Aspartato Oxidasa/metabolismo , Hormona del Crecimiento/biosíntesis , Humanos , N-Metilaspartato/metabolismo , Especificidad por Sustrato
15.
J Cell Biochem ; 120(7): 11044-11055, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30762900

RESUMEN

Excitatory amino acids (EAAs) are found present in the nervous and reproductive systems of animals. Numerous studies have demonstrated a regulatory role for Glutamate (Glu), d-aspartate ( d-Asp) and N-methyl- d-aspartate (NMDA) in the control of spermatogenesis. EAAs are able to stimulate the Glutamate receptors, including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Here in, we assess expression of the main AMPAR subunits, GluA1 and GluA2/3, in the mouse testis and in spermatogonial GC-1 cells. The results showed that both GluA1 and GluA2/3 were localized in mouse testis prevalently in spermatogonia. The subunit GluA2/3 was more highly expressed compared with GluA1 in both the testis and the GC-1 cells. Subsequently, GC-1 cells were incubated with medium containing l-Glu, d-Glu, d-Asp or NMDA to determine GluA1 and GluA2/3 expressions. At 30 minutes and 2 hours of incubation, EAA-treated GC-1 cells showed significantly higher expression levels of both GluA1 and GluA2/3. Furthermore, p-extracellular signal-regulated kinase (ERK), p-Akt, proliferating cell nuclear antigen (PCNA), and Aurora B expressions were assayed in l-Glu-, d-Glu-, and NMDA-treated GC-1 cells. At 30 minutes and 2 hours of incubation, treated GC-1 cells showed significantly higher expression levels of p-ERK and p-Akt. A consequent increase of PCNA and Aurora B expressions was induced by l-Glu and NMDA, but not by d-Glu. Our study demonstrates a direct effect of the EAAs on spermatogonial activity. In addition, the increased protein expression levels of GluA1 and GluA2/3 in EAA-treated GC-1 cells suggest that EAAs could activate ERK and Akt pathways through the AMPAR. Finally, the increased PCNA and Aurora B levels may imply an enhanced proliferative activity.

16.
Mov Disord ; 34(6): 832-844, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30759320

RESUMEN

OBJECTIVE: Spreading depolarization (SD) is a transient self-propagating wave of neuronal and glial depolarization coupled with large membrane ionic changes and a subsequent depression of neuronal activity. Spreading depolarization in the cortex is implicated in migraine, stroke, and epilepsy. Conversely, spreading depolarization in the striatum, a brain structure deeply involved in motor control and in Parkinson's disease (PD) pathophysiology, has been poorly investigated. METHODS: We characterized the participation of glutamatergic and dopaminergic transmission in the induction of striatal spreading depolarization by using a novel approach combining optical imaging, measurements of endogenous DA levels, and pharmacological and molecular analyses. RESULTS: We found that striatal spreading depolarization requires the concomitant activation of D1-like DA and N-methyl-d-aspartate receptors, and it is reduced in experimental PD. Chronic l-dopa treatment, inducing dyskinesia in the parkinsonian condition, increases the occurrence and speed of propagation of striatal spreading depolarization, which has a direct impact on one of the signaling pathways downstream from the activation of D1 receptors. CONCLUSION: Striatal spreading depolarization might contribute to abnormal basal ganglia activity in the dyskinetic condition and represents a possible therapeutic target. © 2019 International Parkinson and Movement Disorder Society.


Asunto(s)
Cuerpo Estriado/fisiopatología , Neuronas Dopaminérgicas/fisiología , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/farmacología , Neuronas/fisiología , Trastornos Parkinsonianos/fisiopatología , Transmisión Sináptica/fisiología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Antiparkinsonianos/farmacología , Cuerpo Estriado/efectos de los fármacos , Compuestos de Mostaza Nitrogenada/metabolismo , Prednisolona/metabolismo , Procarbazina/metabolismo , Ratas , Ratas Wistar , Vincristina/metabolismo
17.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-30925704

RESUMEN

Ras homolog enriched in striatum (Rhes) is a protein that exerts important physiological functions and modulates psychostimulant drug effects. On this basis, the object of this study was to assess 3,4-methylenedioxymethamphetamine (MDMA) effects on microglial (CD11b) and astroglial (GFAP) activation and on dopamine neuron degeneration (TH) in wild-type (WT) and Rhes knockout (KO) male and female mice of different ages. Motor activity was also evaluated. Adult (3 months) MDMA-treated mice displayed an increase in GFAP-positive cells in striatum (STR), whereas the substantia nigra pars compacta (SNc) was affected only in male mice. In these mice, the increase of CD11b was more extensive including STR, SNc, motor cortex (CTX), ventral tegmental area (VTA), and nucleus accumbens (NAc). MDMA administration also affected TH immunoreactivity in both STR and SNc of male but not female WT and Rhes KO mice. In middle-aged mice (12 months), MDMA administration further increased GFAP and CD11b and decreased TH immunoreactivity in STR and SNc of all mice. Finally, MDMA induced a higher increase of motor activity in adult Rhes KO male, but not female mice. The results show that Rhes protein plays an important role on MDMA-mediated neuroinflammation and neurodegeneration dependent on gender and age, and confirm the important role of Rhes protein in neuroinflammatory and neurodegenerative processes.


Asunto(s)
Neuronas Dopaminérgicas/efectos de los fármacos , Proteínas de Unión al GTP/genética , Alucinógenos/efectos adversos , Inflamación/inducido químicamente , N-Metil-3,4-metilenodioxianfetamina/efectos adversos , Enfermedades Neurodegenerativas/inducido químicamente , Factores de Edad , Animales , Neuronas Dopaminérgicas/patología , Femenino , Eliminación de Gen , Inflamación/genética , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Factores Sexuales
18.
J Neurosci ; 36(10): 3064-78, 2016 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-26961959

RESUMEN

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.


Asunto(s)
Envejecimiento , Encéfalo/metabolismo , D-Aspartato Oxidasa/metabolismo , Ácido D-Aspártico/metabolismo , Neuronas/fisiología , Regiones Promotoras Genéticas/genética , Factores de Edad , Animales , Animales Recién Nacidos , Azacitidina/análogos & derivados , Azacitidina/farmacología , Encéfalo/citología , Muerte Celular/genética , D-Aspartato Oxidasa/genética , Decitabina , Embrión de Mamíferos , Inhibidores Enzimáticos/farmacología , Masculino , Metilación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
19.
Neurobiol Dis ; 108: 54-64, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28823933

RESUMEN

N-methyl-d-aspartate receptor (NMDAR) subunit composition strictly commands receptor function and pharmacological responses. Changes in NMDAR subunit composition have been documented in brain disorders such as Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesias (LIDs), where an increase of NMDAR GluN2A/GluN2B subunit ratio at striatal synapses has been observed. A therapeutic approach aimed at rebalancing NMDAR synaptic composition represents a valuable strategy for PD and LIDs. To this, the comprehension of the molecular mechanisms regulating the synaptic localization of different NMDAR subtypes is required. We have recently demonstrated that Rabphilin 3A (Rph3A) is a new binding partner of NMDARs containing the GluN2A subunit and that it plays a crucial function in the synaptic stabilization of these receptors. Considering that protein-protein interactions govern the synaptic retention of NMDARs, the purpose of this work was to analyse the role of Rph3A and Rph3A/NMDAR complex in PD and LIDs, and to modulate Rph3A/GluN2A interaction to counteract the aberrant motor behaviour associated to chronic L-DOPA administration. Thus, an array of biochemical, immunohistochemical and pharmacological tools together with electron microscopy were applied in this study. Here we found that Rph3A is localized at the striatal postsynaptic density where it interacts with GluN2A. Notably, Rph3A expression at the synapse and its interaction with GluN2A-containing NMDARs were increased in parkinsonian rats displaying a dyskinetic profile. Acute treatment of dyskinetic animals with a cell-permeable peptide able to interfere with Rph3A/GluN2A binding significantly reduced their abnormal motor behaviour. Altogether, our findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GluN2A-expressing NMDARs characterizing LIDs. Thus, we suggest that Rph3A/GluN2A complex could represent an innovative therapeutic target for those pathological conditions where NMDAR composition is significantly altered.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Cuerpo Estriado/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/toxicidad , Proteínas del Tejido Nervioso/metabolismo , Trastornos Parkinsonianos/metabolismo , Densidad Postsináptica/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Animales , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/toxicidad , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/patología , Femenino , Humanos , Levodopa/uso terapéutico , Macaca mulatta , Masculino , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Oxidopamina , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/patología , Densidad Postsináptica/efectos de los fármacos , Densidad Postsináptica/patología , Unión Proteica/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Técnicas de Cultivo de Tejidos , Proteínas de Transporte Vesicular/antagonistas & inhibidores , Rabfilina-3A
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