Biology subjects

Vezzoli, E.

Publications and source records attributed to Vezzoli, E..

5 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↗

bioRxiv2023

Tactile Sensitivity to the Frequency Spectrum of Complex Vibrotactile Signals

Haptic interactions with objects induce complex vibrotactile signals that are central to tactile perception. Despite the broad literature on vibrotactile perception, there is surprisingly little knowledge of the sensory processing of complex tactile signals made of multiple frequencies. To fill this gap, the study reported here investigated the impact of the constitutive pure tones of a complex vibrotactile signal on its perception. Participants completed a 3-AFC task, in which they were asked to identify an odd signal among two complex references. The odd signal was created by removing one pure tone from the reference, which varied in spectral composition, harmonicity, and inter-frequency intervals. Each reference signal was made of either two, three, or four pure tones. The results revealed that the removed pure tones value as well as the inter-frequency interval play a significant role on participants performance whereas changes in harmonicity, complexity have little impact. In addition, the results showed that the smaller the ratio between the removed frequency and the lowest one of the reference signals, the better the participants capacity to identify the one with a missing tone. Overall, the detection of a missing tone in a complex signal predominantly depends on the tones frequency value of the removed signal suggesting a tactile sensitivity to the frequency spectrum of complex vibrotactile signals. NEW & NOTEWORTHYThis research reports an investigation of the respective roles of frequency range, harmonicity, and complexity on human perception of vibrotactile signals. The results revealed that only pure tones that are close to the lower end of the frequency spectrum are noticed when they are missing. This finding sheds new light on the mechanisms of frequency selectivity in touch.

neuroscience↗

bioRxiv2023

Generation of human cerebral organoids with a structured outer subventricular zone

Mammalian outer radial glia (oRG) emerge as cortical progenitor cells that directly support the development of an enlarged outer subventricular zone (oSVZ) and, in turn, the expansion of the neocortex. The in vitro generation of oRG is essential to model and investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 pathway using LIF, which is not produced in guided cortical organoids, we developed a cerebral organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The structured oSVZ is composed of progenitor cells expressing specific oRG markers such as GFAP, LIFR, HOPX, which closely matches human oRG in vivo. In this microenvironment, cortical neurons showed faster maturation with enhanced metabolic and functional activity. Incorporation of hPSC-derived brain vascular LIF- producing pericytes in cerebral organoids mimicked the effects of LIF treatment. These data indicate that the cellular complexity of the cortical microenvironment, including cell-types of the brain vasculature, favors the appearance of oRG and provides a platform to routinely study oRG in hPSC-derived brain organoids.

developmental biology↗

bioRxiv2021

Modeling autism-associated SHANK3 deficiency using human cortico-striatal organoids generated from single neural rosettes

Our understanding of the human brain is limited by the lack of experimental models to mechanistically probe the properties of brain cells at different developmental stages under normal and pathological conditions. We developed a new method for generating human cortico-striatal organoids from stem cell-derived single neural rosettes (SNRs) and used it to investigate cortico-striatal development and deficits caused by the deficiency of an autism- and intellectual disability-associated gene SHANK3. We show that SNR-derived organoids consist of different cortico-striatal cells, including pallial and subpallial progenitors, primary cortical and striatal neurons, interneurons, as well as macroglial and mural cells. We also demonstrate that neurons in SNR-derived organoids are predictably organized, functionally mature, and capable of establishing functional neural networks. Interestingly, we found that the cellular and electrophysiological deficits in SHANK3-deficient SNR-derived organoids are dependent on the level of SHANK3 expression and that organoids with complete hemizygous SHANK3 deletion have disrupted expression of several clustered protocadherins and multiple primate-specific zinc-finger genes. Together, this study describes a new method for using SNRs to generate organoids, provides new insights into the cell lineages associated with human cortico-striatal development, and identifies specific molecular pathways disrupted by hemizygous SHANK3 deletion, which is the most common genetic abnormality detected in patients with 22q13 deletion syndrome.

neuroscience↗

bioRxiv2020

Dose-dependent and disease-modifying effects of striatal infusion of cholesterol in Huntington's disease

A variety of pathophysiological mechanisms are implicated in Huntingtons disease (HD). Among them, reduced cholesterol biosynthesis has been detected in the HD mouse brain from pre-symptomatic stages, leading to diminished cholesterol synthesis, particularly in the striatum. In addition, systemic injection of cholesterol-loaded brain-permeable nanoparticles ameliorates synaptic and cognitive function in a transgenic mouse model of HD. To identify an appropriate treatment regimen and gain mechanistic insights into the beneficial activity of exogenous cholesterol in the HD brain, we employed osmotic mini-pumps to infuse three escalating doses of cholesterol directly into the striatum of HD mice in a continuous and rate-controlled manner. All tested doses prevented cognitive decline, while amelioration of disease-related motor defects was dose-dependent. In parallel, we found morphological and functional recovery of synaptic transmission involving both excitatory and inhibitory synapses of striatal medium spiny neurons. The treatment also enhanced endogenous cholesterol biosynthesis and clearance of mutant Huntingtin aggregates. These results indicate that cholesterol infusion to the striatum can exert a dose-dependent, disease-modifying effect and may be therapeutically relevant in HD.

neuroscience↗