Biology subjects

Attanasio, S.

Publications and source records attributed to Attanasio, S..

4 recordsLinked to original sources

bioRxiv2025

MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation

Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In MECP2 Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the de novo purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders. Metabolic control is fundamental to cellular function, influencing energy production, signaling, epigenetic regulation, and tissue homeostasis1. Nowhere is this more critical than in the brain, where tightly regulated metabolic networks sustain high energetic demands and support neuronal development, synaptic plasticity, and circuit formation2. Disruptions in these networks are increasingly implicated across a spectrum of neurodevelopmental disorders3-5, yet their precise metabolic signatures and mechanistic contributions remain poorly understood.

neuroscience↗

bioRxiv2025

SOuLMuSiC: A Computational Tool for Predicting the Impact of Mutations on Protein Solubility

Protein solubility problems arise in a wide range of applications, from antibody development to enzyme production, and are linked to several major disorders, including cataracts and Alzheimers diseases. To assist scientists in designing proteins with improved solubility and better understand solubility-related diseases, we introduce SOuLMuSiC, a computational tool for the fast and accurate prediction of the impact of mutations on protein solubility. Our model is based on a simple shallow artificial neural network that takes as input a series of features, including biophysical properties of wild-type and mutated residues, energetic values computed using various statistical potentials, and mutational scores derived from protein language models. SOuLMuSiC has been trained on a curated dataset of about seven hundred mutations with known solubility values, collected and manually verified from original literature. It significantly outperforms current state-of-the-art predictors in strict cross-validation and shows good performance on external datasets containing high-throughput enzyme solubility-related data as well as protein aggregation propensities. In summary, SOuLMuSiC is a valuable tool for identifying mutations that impact protein solubility, and can play a major role in the rational design of proteins with improved solubility and in understanding genetic variants effect. It is freely available for academic use at http://babylone.ulb.ac.be/SoulMuSiC/.

bioinformatics↗

bioRxiv2024

WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer

It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.

cancer biology↗

bioRxiv2020

CHOP-c-JUN complex plays a critical role in liver proteotoxicity induced by mutant Z alpha-1 antitrypsin.

Alpha-1 antitrypsin (AAT) deficiency is a common genetic disorder with lung and liver involvement. Most patients carry the Z allele in SERPINA1 that encodes a mutant AAT (ATZ) forming hepatotoxic polymers. We found CHOP upregulation and activation in both mouse (PiZ) and human livers expressing ATZ. Compared to controls, juvenile PiZ/Chop-/- mice showed reduction in hepatic ATZ and transcriptional response to endoplasmic reticulum stress, as consequence of CHOP-mediated increase of SERPINA1 transcription. CHOP was found to upregulate SERPINA1 though binding with c-JUN on SERPINA1 regulatory elements, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. Compared to adults, AAT deficiency in infants has different severity and prognosis. Based on our findings, CHOP-c-JUN complex upregulates SERPINA1 transcription and play an important role in the hepatic disease pathogenesis by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.

genetics↗