Biology subjects

Nuzzo, T.

Publications and source records attributed to Nuzzo, T..

5 recordsLinked to original sources

bioRxiv2025

Deep Brain Stimulation rescues the homeostasis disruption of circulating D- and L-amino acids level in men with Parkinson's Disease.

Recent evidence indicates a marked downregulation of circulating D- and L-amino acids involved in regulating glutamatergic NMDAR function in Parkinsons disease (PD) patients compared with matched controls. However, the extent to which disease progression and antiparkinsonian therapies contribute to this dysregulation remains unclear. To address these issues, in the present study we measured by High Performance Liquid Chromatography the concentrations of glutamatergic system-related D- and L-amino acids and their precursors in the plasma of male and female healthy controls (HC) and PD patients across three distinct clinical stages and treatment conditions: (1) early stage L-DOPA naive patients treated with MAO-B inhibitors; (2) mid-stage patients treated with L-DOPA; and (3) advanced stage patients receiving Deep Brain Stimulation in the subthalamic nucleus (STN-DBS) plus L-DOPA. Our results reveal notable reduction of circulating neuroactive D- and L-amino acids exclusively in male PD patients, while female patients exhibit a similar directional trend. In male patients, this dysregulation manifests early, with L-DOPA-naive individuals showing decreased plasma levels of L-glutamate and L-aspartate. In mid-stage L-DOPA-treated PD patients, amino acid reductions extend to L-alanine, L-serine, L-glutamine, L-asparagine, and L-threonine. Remarkably, in advanced PD patients, with a median disease duration of [~] 23 years, STN-DBS normalizes the blood concentrations of these amino acids to those observed in HC. In conclusion, our study highlights the potential of circulating D- and L-amino acid dysregulation as an early biomarker of PD and demonstrates that, in contrast to L-DOPA therapy, the STN-DBS confers systemic metabolic benefits even at advanced stages of the disease.

neuroscience↗

bioRxiv2025

Ultra-performance liquid chromatography-mass spectrometry analysis of post-mortem brain tissue reveals specific amino acid profile dysregulation in Parkinson's Disease and Alzheimer's Disease patients

BackgroundCombined metabolomic and HPLC-based analyses have identified significant metabolic alterations in serum and plasma amino acid levels of Parkinsons disease (PD) patients, underscoring their potential as biomarkers. However, it remains unclear whether these biochemical changes also manifest within the central nervous system or are confined to peripheral metabolism, reflecting systemic metabolic disturbances. MethodsTo address this issue, here we measured the levels of 44 different amino acids in post-mortem brain samples from MPTP-intoxicated, L-DOPA-treated monkeys and PD patients at different Braak Lewy body (LB) stages, compared to their respective controls, through targeted Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). ResultsIn MPTP-intoxicated monkeys, UPLC-MS revealed significant elevations in GABA, citrulline, threonine, isoleucine, phenylalanine, valine, glycine, and serine in the putamen, whereas we failed to detect alterations in the superior frontal gyrus (SFG). In PD patients, caudate-putamen (CPu) analysis demonstrated consistent serine upregulation across Braak LB stages 3-4 and 6, with stage 6 specifically showing additional proline increases and phosphoethanolamine decreases. Notably, serine was the sole amino acid significantly altered in both the putamen of MPTP-intoxicated monkeys and the CPu of PD patients. No significant amino acid alterations were observed in the SFG of PD patients, mirroring the findings in monkeys. In contrast, Alzheimers disease (AD) patient SFG samples showed significant increases in tryptophan, phenylalanine, threonine, tyrosine, and methionine relative to controls. ConclusionsThese findings demonstrate that cerebral amino acid alterations in PD are region-specific and primarily localized to brain areas receiving nigrostriatal dopaminergic innervation. Moreover, the cortical amino acid profile in AD differs substantially from that in PD, suggesting disease-specific metabolic signatures in distinct neurodegenerative conditions.

neuroscience↗

bioRxiv2025

Chiral shift toward D-serine reflects intrathecal inflammation in multiple sclerosis and counteracts motor impairment in a murine model

Multiple sclerosis (MS) is characterized by chronic inflammatory demyelination involving complex interplay between the central nervous and immune systems. Neuroinflammation triggers cellular reorganization requiring O_SCPLOWLC_SCPLOW-serine for sustained syntheses of membrane lipids and nucleic acids, whereas it causes aberrant glutamatergic neurotransmission involving O_SCPLOWDC_SCPLOW-serine. However, significance of serine metabolism in MS pathology remains unexplored. Here we show that serine chiral homeostasis is disrupted in MS and endogenous O_SCPLOWDC_SCPLOW-serine prevents motor deficits caused by inflammatory demyelination. We found in a large cohort study that patients with MS exhibit elevated O_SCPLOWDC_SCPLOW-serine levels and the O_SCPLOWDC_SCPLOW-/total serine ratio in the cerebrospinal fluid at diagnosis. Steric deviation toward O_SCPLOWDC_SCPLOW-serine accords with emergence of the intrathecal inflammatory marker oligoclonal bands, and correlates negatively with proinflammatory cytokines. An in vivo animal model of MS, genetically engineered to exhibit distinct metabolic states of O_SCPLOWDC_SCPLOW-serine, revealed that endogenous O_SCPLOWDC_SCPLOW-serine synthesis mitigates the progression of motor deficits and suppresses proinflammatory and vascular endothelial pathogenic signaling. Moreover, pre-symptomatic oral supplementation with O_SCPLOWDC_SCPLOW-serine, but not O_SCPLOWLC_SCPLOW-serine, enhances production of extracellular matrices, preserves integrity of the blood brain barrier, attenuates demyelination, and improves motor function. Contrary to the previously recognized neurotoxic nature of O_SCPLOWDC_SCPLOW-serine, our findings reveal an unrecognized significance of O_SCPLOWDC_SCPLOW-serine metabolism in MS and a protective function of O_SCPLOWDC_SCPLOW-serine against neuroinflammation involving disruption of the blood brain barrier, which may present an untapped therapeutic target in MS. One Sentence SummarySerine chiral homeostasis is disturbed in multiple sclerosis and O_SCPLOWDC_SCPLOW-serine mitigates inflammatory demyelination.

neuroscience↗

bioRxiv2025

Tandem Mass Tag-Based High-Resolution LC-MS/MS identifies free D-aspartate-induced expression of proteins linked to schizophrenia and autism spectrum disorder

D-aspartate is an endogenous agonist of NMDA and mGlu5 receptors, with a distinctive spatiotemporal expression profile that peaks in the prenatal and early postnatal brain. This suggests a critical role for D-aspartate metabolism in modulating neurodevelopmental processes linked to glutamatergic neurotransmission. However, the precise mechanisms through which D-aspartate exerts its effects remain unclear. To elucidate the molecular pathways orchestrated by early D-aspartate signalling, we employed a knockin mouse model characterized by constitutive D-aspartate depletion due to the prenatal expression of its degradative enzyme, D-aspartate oxidase. Using an advanced quantitative proteomic approach based on Tandem Mass Tag isobaric labelling and nano-liquid chromatography coupled with high-resolution tandem mass spectrometry, we investigated the proteomic variations induced by D-aspartate depletion during postnatal brain development comparing Ddo knockin mice with their wild-type littermates. Our findings reveal that D-aspartate modulates the neonatal expression of proteins involved in glutamatergic neurotransmission, nervous system development, and cytoskeleton organization. Moreover, proteomic analysis identified a subset of D-aspartate-regulated proteins mapping molecular pathways associated with autism spectrum disorder and schizophrenia. These findings offer new perspectives on the complex protein networks influenced by D-aspartate metabolism in the developing brain and highlight its potential impact on cerebral function in health and psychiatric disorders.

biochemistry↗

bioRxiv2024

Dysregulated balance of D- and L-amino acids modulating glutamatergic neurotransmission in severe spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to motor neuron survival, SMN deficiency affects the integrity and function of afferent synapses that provide glutamatergic excitatory drive essential for motor neuron firing and muscle contraction. However, it is unknown whether deficits in the metabolism of excitatory amino acids and their precursors contribute to neuronal dysfunction in SMA. To address this issue, we measured the levels of the main neuroactive D- and L-amino acids acting on glutamatergic receptors in the central nervous system of SMN{Delta}7 mice as well as the cerebrospinal fluid (CSF) of SMA patients of varying severity before and after treatment with the SMN-inducing drug Nusinersen. Our findings reveal that SMN deficiency disrupts glutamate and serine metabolism in the CSF of severe SMA patients, including decreased concentration of L-glutamate, which is partially corrected by Nusinersen therapy. Moreover, we identify dysregulated L-glutamine to L-glutamate conversion as a shared neurochemical signature of altered glutamatergic synapse metabolism that implicates astrocyte dysfunction in both severe SMA patients and mouse models. Lastly, consistent with a correlation of higher CSF levels of D-serine with better motor function in severe SMA patients, we show that daily supplementation with the NMDA receptor co-agonist D-serine improves neurological deficits in SMN{Delta}7 mice. Altogether, these findings provide direct evidence for dysregulation of D- and L-amino acid metabolism linked to glutamatergic neurotransmission in severe SMA and have potential implications for treating this neurological disorder.

neuroscience↗