Biology subjects

Di Angelantonio, S.

Publications and source records attributed to Di Angelantonio, S..

6 recordsLinked to original sources

bioRxiv2025

Missense mutations on SynGAP C2 domain impair membrane diffusion

SYNGAP1 mutations have been linked to a range of neuropathological disorders and, more recently, to the insurgence of cancer. Despite its emerging relevance, the molecular basis of SynGAPs action remains poorly understood. Here, using extensive molecular dynamics simulations integrated with structural analysis, we define how the SynGAP C2 domain associates with lipid bilayers. In particular, we observed spontaneous membrane binding of the domain in two distinct orientations, top and side, defined by the relative positioning of the C2 domain to its fold. These modes display markedly different dynamical properties: the top mode enables faster lateral diffusion on the membrane surface, whereas the side mode establishes more stable but less mobile contacts. Interestingly, pathogenic missense mutations mapping to the membrane-facing loops of SynGAP C2 disrupt these dynamics, leading to reduced diffusivity and altered membrane avidity. Our findings reveal a dual binding mechanism that underlies SynGAPs membrane versatility and offer a general framework for how diverse mutations may perturb SynGAP activity across its polyedric biological functions.

biophysics↗

bioRxiv2024

Bezafibrate treatment rescues neurodevelopmental and neurodegenerative defects in 3D cortical organoid model of MAPT frontotemporal dementia

INTRODUCTIONThe intronic MAPT mutation IVS10+16 is linked to familiar frontotemporal dementia, causing hyperphosphorylation and accumulation of tau protein, resulting in synaptic and neuronal loss and neuroinflammation in patients. This mutation disrupts MAPT gene splicing, increasing exon 10 inclusion and leading to an imbalance of 3R and 4R Tau isoforms. METHODSWe generated patterned cortical organoids from isogenic control and mutant human iPSC lines. Nanostring gene expression analysis immunofluorescence and calcium imaging recordings were used to study the impact of the MAPT IVS10+16 mutation on neuronal development and function. RESULTSTau mutant cortical organoids showed altered mitochondrial function and gene expression related to neuronal development, with synaptic markers and neuronal activity reduction. Bezafibrate treatment, which restored mitochondrial content, rescued synaptic functionality and tau physiology. DISCUSSIONThese findings suggest that targeting mitochondrial function with bezafibrate could potentially reverse tau-induced neurodevelopmental deficits, highlighting its therapeutic potential for tauopathies like FTD. HIGLIGHTSO_LIThe IVS 10+16 MAPT mutation significantly disrupts cortical differentiation and synaptic maturation, evidenced by downregulated genes associated with synapses and neuronal development. C_LIO_LITau-mutant cortical organoids exhibit mitochondrial dysfunction, with fewer and smaller mitochondria alongside with tau hyperphosphorylation and aggregation, which further contribute to neuronal damage and disease progression. C_LIO_LITreatment with bezafibrate effectively normalizes mitochondrial parameters, enhances neuronal integrity and synaptic maturation, and restores network functionality, showcasing its promise as a therapeutic strategy for tauopathies. C_LIO_LIThe 3D in vitro disease model used in this study proves valuable for studying tauopathies and testing new drugs, effectively mimicking key aspects of tau-related neurodegeneration. C_LI RESEARCH IN CONTEXTO_LISystematic Review: We searched PubMed, Google Scholar, and Web of Science for studies on the MAPT IVS10+16 mutations impact on tauopathies, focusing on neuronal development, synaptic function, and mitochondrial involvement. Key terms included "MAPT IVS10+16 mutation," "tauopathy," "neuronal development," "synaptic function," and "mitochondrial function." C_LIO_LIInterpretation: Our findings reveal that the MAPT IVS10+16 mutation disrupts mitochondrial function altering gene expression related to neuronal development, synaptic structures, impairing neuronal and glial maturation. Bezafibrate treatment restored mitochondrial content, synaptic functionality, and tau physiology in mutant-derived cortical organoids, suggesting it as a potential therapeutic strategy for tauopathies. C_LIO_LIFuture Directions: Future research should investigate the molecular mechanisms underlying the bezafibrates therapeutic effect and its long-term efficacy and safety in vivo, in humanized mouse models. Additionally, the possibility to combine bezafibrate with other therapeutic agents used to treat tauopathies will be worth to assess. C_LI

neuroscience↗

bioRxiv2022

Reactive microglia and cytokine release entails microtubule remodeling from acentrosomal to centrosomal arrays

Microglia reactivity entails a large-scale remodeling of cellular geometry, but the role of the microtubule cytoskeleton during these changes remains unexplored. Here we show that reactive proinflammatory microglia provide a heretofore unique example of microtubule reorganization from a non-centrosomal array of parallel and stable microtubules to a radial array of more dynamic microtubules. While in the homeostatic state microglia nucleate microtubules at Golgi outposts, proinflammatory signaling induces recruitment of nucleating material nearby the centrosome and inhibition of centrosomal maturation enhances NLRP3 inflammasome activation and secretion of IL-1{beta}. Our results demonstrate that a hallmark of microglia reactivity is a striking remodeling of the microtubule cytoskeleton and suggest that pericentrosomal microtubule nucleation may serve as a distinct marker of microglia activation as well as a novel target to modulate cytokine-mediated inflammatory responses in chronic disease and tissue injury.

cell biology↗

bioRxiv2021

Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

Complement signaling is thought to serve as an opsonization signal to promote the phagocytosis of synapses by microglia. However, while its role in synaptic remodeling has been demonstrated in the retino-thalamic system, it remains unclear whether complement signaling mediates synaptic pruning in the brain more generally. Here we show that mice lacking the complement 3 receptor (C3r), the major microglia complement receptor, fail to show a deficit in either synaptic pruning or axon elimination in the developing mouse cortex. Instead, mice lacking C3r show a deficit in the perinatal elimination of neurons, both in the retina as well as in the cortex, a deficit that is associated with increased cortical thickness and enhanced functional connectivity in these regions in adulthood. These data demonstrate a preferential role for complement in promoting neuronal elimination in the developing brain and argue for a reconsideration of the role of complement in synaptic pruning.

neuroscience↗

bioRxiv2021

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglial cells are active players in regulating synaptic development and plasticity in the brain. However, how these cells influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological depletion of microglia, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features accompanied by higher levels of plasticity. In addition, microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. Remarkably, microglial repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in synaptic organization and activity of glutamatergic synapses.

neuroscience↗

bioRxiv2020

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models, however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show increased proliferation of GFAP positive cells, likely astrocytes, increased spontaneous network activity and depolarizing GABAergic transmission. Cortical brain organoid models show increased proliferation of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

neuroscience↗