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April 20th, 2025
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Proteomic and mass spectrometry laboratory, Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi V
biochemistry
biorxiv

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

Errico, F.Open in Google Scholar•Russo, R.Open in Google Scholar•Carrillo, F.Open in Google Scholar•Nuzzo, T.Open in Google Scholar•di Vito, R.Open in Google Scholar•Canonico, E.Open in Google Scholar•Pedone, P. V.Open in Google Scholar•Di Cunto, F.Open in Google Scholar•Esposito, T.Open in Google Scholar•Usiello, A.Open in Google Scholaret al.

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. Keywords: High-resolution mass spectrometry, proteomics, Tandem Mass Tag, D-aspartate oxidase, D-aspartate, autism spectrum disorder, schizophrenia.

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