Biology subjects

Cordiglieri, C.

Publications and source records attributed to Cordiglieri, C..

4 recordsLinked to original sources

bioRxiv2026

Structure-function dissection of huntingtin exon 1 identifies a PRD-driven modifier of neuronal toxicity in Huntington's disease

The Huntingtin gene (HTT) contains a conserved, yet expandable CAG repeat within exon 1. While the pathogenic expansion in Huntingtons Disease (HD) is well studied, the role of surrounding domains remains unclear. Using genome-edited mini-organoids and neurons, we dissected HTT exon 1 and found species-specific toxicity: the human variant caused more severe deficits than the mouse. Swapping the proline-rich domain (PRD) - the most divergent region - revealed its key role: the mouse PRD mitigated, while the human PRD worsened neuronal phenotypes. Omics profiling showed that pathogenic human exon 1 induced broad protein dysregulation, largely reversed by mouse PRD replacement. Bioinformatics implicated the actin cytoskeleton and transcriptional coactivator MKL2/MRTFB. We validated MKL2/MRTFB dysregulation in HD models and showed that restoring its expression rescued neuronal abnormalities. These findings highlight the PRDs contribution to HD toxicity and point to MKL2/MRTFB and the cytoskeleton as candidate mediators.

neuroscience↗

bioRxiv2025

Targeted Antisense Oligonucleotide Treatment Rescues Developmental Alterations in Spinal Muscular Atrophy Organoids

Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type I donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that restored SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in newly identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing new insights for optimizing treatment strategies.

neuroscience↗

bioRxiv2024

Regulatory T-cells in multiple sclerosis are activated by Epstein-Barr Virus and produce IL-10 in the central nervous system

Regulatory T-cells (Tregs) maintain immune homeostasis, but antigens activating adaptive Tregs in human pathologies are ill-defined. EOMES+type-1 regulatory (Tr1)-like T-cells had a dysregulated homeostasis in multiple sclerosis (MS), which was related to their activation in the central nervous system (CNS). EOMES+Tr1-like cells were enriched and clonally expanded in patients cerebrospinal fluid (CSF) and were the major IL-10-producing T-cell subset in the CNS. Regulatory T-cells from PwMS produced IL-10 and IFN-{gamma} with antigens derived from Epstein-Barr Virus (EBV), but not from myelin. EOMES+Tr1-like cells responded selectively to the latency-associated antigen EBNA1, whereas FOXP3+Tregs and Th1-cells responded also to lytic EBV antigens. EBNA1-specific EOMES+Tr1-like cells were present in patients carrying the HLA-DRB1*15:01 risk allele, were associated with anti-EBNA1 IgG and disappeared upon therapeutic B-cell depletion. IL-10+EOMES+Tr1-like were present in MS brain lesions, and some were in the vicinity of EBV-infected B-cells and CD8+T-cells. Notably, EOMES+Tr1-like cells suppressed CD8+T-cell activation by EBV-infected B-cells. We propose that the insufficient protective functions of Tregs in MS are due to their aberrant anti-viral specificities that promote immune escape of a disease-associated virus.

immunology↗

bioRxiv2020

SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in Huntington's disease

Brain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntingtons Disease (HD). One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway. Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the N-terminal fragment of human SREBP2 (hSREBP2). Robust hSREBP2 expression in striatal glial cells in HD mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed Drd2 transcript levels decline, cleared muHTT aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in HD brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of HD.

neuroscience↗