Biology subjects

Frattini, V.

Publications and source records attributed to Frattini, V..

3 recordsLinked to original sources

bioRxiv2023

Translational modulation by ISRIB alleviates synaptic and behavioral phenotypes in Fragile X syndrome

Fragile X syndrome (FXS) is caused by the functional loss of Fragile X messenger ribonucleoprotein (FMRP), a translational regulator that binds the transcripts of many proteins involved in synaptic function and plasticity. Dysregulated protein synthesis is a central effect of FMRP loss and to date direct translational modulation has not been leveraged in the treatment of FXS. Thus, we examined the effect of the small molecule translational modulator, Integrated Stress Response Inhibitor (ISRIB), in treating synaptic and behavioral symptoms of FXS. Using a combination of population-level single synapse analysis, in vivo two-photon microscopy, and behavioral analysis, we revealed a mechanism for the appearance of dense and immature dendritic spines, which are observed in human FXS patients and Fmr1 knockout (KO) mice. Our data suggest that FMRP loss at the synapse dysregulates synaptic protein abundance and that spines are disproportionately stabilized through increased PSD-95 expression but prevented from maturing through reduced synaptic accumulation of glutamate receptors. ISRIB rescues these molecular and synaptic deficits in FXS and improves social recognition in Fmr1 KO mice. These findings highlight the therapeutic potential of targeting core translational mechanisms and the differential impact of FMRP on synaptic and cellular function in FXS and neurodevelopmental disorders more broadly.

neuroscience↗

bioRxiv2023

Human USP18 protects diverse cancer lineages from Type I Interferon independently of its canonical catalytic function

Precise temporal regulation of Type I interferon signaling is imperative to effectively fight infections and cancerous cells without triggering autoimmunity. The key negative regulator of Type I interferon signaling is ubiquitin-specific protease 18 (USP18). USP18 cleaves interferon-inducible ubiquitin-like modifications through its canonical catalytic function and directly inhibits interferon receptor signaling through its scaffold role. USP18 loss-of-function dramatically impacts autoimmune disease, viral susceptibility, and cancer cell survival. However, the relative contribution of catalytic versus scaffold function is unresolved and must be determined to design effective therapeutics targeting USP18. To precisely delineate individual contribution, we evaluated the functional impact of single amino acid mutations that disrupt catalytic or scaffold activity. Here we demonstrate catalytic activity does not contribute to cell autonomous Type I interferon sensitivity across multiple cancer cell lineages. Furthermore, introducing a patient-derived mutation that disrupts scaffold function is sufficient to inhibit cancer growth. These findings establish a fundamental mechanistic basis for USP18 therapeutic design across diseases. OVERVIEWO_LIUSP18 is the key negative regulator of Type I interferon signaling in humans, mediating autoimmune disease, viral susceptibility, and cancer cell survival. C_LIO_LIUSP18 cleaves interferon-inducible ubiquitin-like modifications through its canonical catalytic function and attenuates interferon receptor signaling through its scaffold role. C_LIO_LIDelineating the contribution of each function is critical to resolve the mechanistic basis of interferon regulation and enable the development of therapeutics targeting USP18. C_LIO_LIWe demonstrate that cell intrinsic interferon sensitivity is not mediated by loss of catalytic activity. However, disruption of scaffold function by a patient-specific mutation inhibits cancer cell growth. C_LIO_LIFurthermore, we discovered that canonical catalytic activity is surprisingly inefficient in human cells. C_LIO_LIThese results clarify a fundamental mechanism of immune regulation and cancer cell survival in humans. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/533924v3_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@d0a353org.highwire.dtl.DTLVardef@192a09dorg.highwire.dtl.DTLVardef@16eb296org.highwire.dtl.DTLVardef@8e98a3_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Single-Cell Transcriptome Analysis of Lineage Diversity and Microenvironment in High-Grade Glioma

BackgroundDespite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs with massively-parallel single-cell RNA-Seq.\n\nResultsWhile HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.\n\nConclusionsThese studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.

cancer biology↗