Biology subjects

Turrini, G.

Publications and source records attributed to Turrini, G..

3 recordsLinked to original sources

bioRxiv2026

Functional validation of allele-specific LMNB1 silencing in patient-derived astrocytes as a therapeutic option for Autosomal Dominant Leukodystrophy

Adult-onset Autosomal Dominant Leukodystrophy (ADLD) is a rare fatal leukodystrophy caused by increased LMNB1 gene dosage, most commonly resulting from duplication of the LMNB1 locus. Because ADLD is a gene dosage disorder, selective reduction of pathological LMNB1 expression represents a rational therapeutic strategy. Although allele-specific RNA interference has previously been shown to lower LMNB1 levels in patient-derived fibroblasts and directly reprogrammed neurons, its therapeutic effects have not been evaluated in disease-relevant human glial cells or using functional efficacy endpoints. Here, we established human induced pluripotent stem cell-derived astrocytes from ADLD patients as a human glial model in which to validate allele-specific LMNB1 silencing across molecular, cellular, and functional readouts. ADLD astrocytes recapitulated increased LMNB1 expression and characteristic nuclear abnormalities and displayed transcriptional alterations affecting extracellular matrix organization, calcium homeostasis, metabolism and RNA processing. Functionally, these cells also exhibited functional phenotypes suitable for therapeutic evaluation: astrocyte-conditioned medium impaired the viability of both murine and human oligodendroglial cultures, while conditioned-medium and direct astrocyte-seeding paradigms revealed impaired post-lesion myelin recovery in lysolecithin-treated cerebellar organotypic slices. Allele-specific LMNB1 silencing restored physiological LMNB1 levels, corrected nuclear abnormalities, attenuated astrocyte-mediated oligodendroglial toxicity, improved post-lesion myelin recovery, and was associated with selective transcriptional programs associated with extracellular support and cholesterol metabolism. Together, these findings provide molecular, cellular, and functional validation of allele-specific LMNB1 dosage correction in patient-derived human astrocytes and offer key support for LMNB1-lowering strategies in disease-relevant human glial cells.

neuroscience↗

bioRxiv2025

Brain injury reactivates a developmental program driving genesis and integration of transient LGE-class interneurons

Brain lesions can unlock a latent neurogenic potential in parenchymal astrocytes. However, the identity of their neuronal progeny has remained unclear. Here, we show that neurons generated by striatal astrocytes following excitotoxic lesions are transient, yet they reach advanced stages of morphological and functional maturation and integrate into cortico-striatal-thalamic circuits. Single-cell RNA-seq mapping onto an embryonic reference revealed that these cells are not related to adult striatal neuron types but instead belong to the LGE-MEIS2/PAX6 interneuron class. Notch abrogation, which mimics neurogenic activation, drives both cortical and striatal astrocytes toward this same interneuron class, revealing a shared intrinsic commitment. In primates, LGE-MEIS2/PAX6 cells transiently populate the embryonic striatum and cortex, and through spatial transcriptomics, we reveal that in mice these cells are also present and widely distributed throughout the telencephalon during embryonic and postnatal development. Thus, unlike other vertebrates in which adult telencephalic astroglia preserve the potential to generate constitutive region-specific neurons, the homologous cells in mammals converge on the generation of a specific transient neuron class, possibly representing a reservoir for circuit plasticity in adult life.

neuroscience↗

bioRxiv2025

A single-cell transcriptomic atlas maps cerebellar astrocyte diversity and uncovers the transcriptional code underlying their maturation trajectories

Astrocytes are increasingly recognized as key regulators of neural circuit development and function, with mounting evidence revealing substantial heterogeneity within and across brain regions. Yet, the full extent of this diversity and its developmental mechanisms remain poorly understood. To address this, we leveraged the uniqueness of the mouse cerebellum, which hosts well-defined astrocyte types and established progenitor pools. Through complementary multi-modal omic approaches, including single-cell RNA sequencing, spatial transcriptomics, trajectory inference, clonal lineage reconstruction, and gene expression and regulatory network analyses, we systematically dissected the molecular diversity and ontogenesis of cerebellar astrocytes. We identified known types and uncovered new subtypes with functional specialization, inferring their developmental trajectories from multiple embryonic niches and postnatal progenitor sources with fate divergence, convergence, and restriction. We further predicted a hierarchical transcriptional regulator code governing this diversification, operating at multiple levels: distinct regulatory modules i) reflect embryonic regionalization and lineage; ii) determine broad astroglial identity; specify iii) Bergmann versus non-Bergmann fates; and guide iv) astrocyte type and v) subtype acquisition. Our findings map and temporally organize transcriptional programs that capture key determinants of astrocyte fate, integrating them along defined trajectories toward diverse astrocyte identities. This high-resolution framework for cerebellar glial diversification offers a model to be challenged across other brain regions.

neuroscience↗