Biology subjects

Tiberi, M.

Publications and source records attributed to Tiberi, M..

6 recordsLinked to original sources

bioRxiv2026

TRIM9 Determines Sex-Specific β-Amyloid/Cellular Prion Protein/mGluR5 Complex Formation and Pathological Signaling in Alzheimer's Disease Mice

Biological sex is a major determinant of Alzheimers disease prevalence, yet the molecular mechanisms underlying sex-specific vulnerability remain largely unknown. Metabotropic glutamate receptor 5 (mGluR5) functions as a co-receptor for {beta}-amyloid (A{beta}42) oligomer/cellular prion protein (PrPC)-mediated pathogenic signaling in males but not females, establishing a sex-dimorphic node in {beta}-amyloid pathophysiology whose regulatory basis is undefined. Using quantitative proteomic analysis, we identify the E3 ubiquitin ligase TRIM9 as a novel mGluR5-interacting protein and a previously unrecognized sex-specific regulator of the A{beta}42/PrPC/mGluR5 complex. TRIM9 selectively associates with mGluR5 in male but not female APP/PS1 mouse brain and is required for mGluR5 to serve as a co-receptor for PrPC-dependent A{beta}42 oligomer binding. Genetic deletion of TRIM9 abolishes A{beta}42/PrPC/mGluR5 complex assembly in male APP/PS1 mice demonstrating that TRIM9 is an essential scaffold for male-specific A{beta}42 signal transduction. Loss of TRIM9 in males further reduces {beta}-amyloid pathology by restoring Akt/GSK3{beta}/ZBTB16-dependent autophagic flux, linking disruption of this complex to a defined downstream proteostatic mechanism. Together, these findings establish TRIM9 as a critical molecular determinant coupling male-specific A{beta}42/PrPC/mGluR5 complex assembly to downstream neurodegenerative signaling and {beta}-amyloid pathology. They reveal an unappreciated layer of sex-dependent complexity in mGluR5 pharmacology and identify disruption of the TRIM9/mGluR5 interaction as a potential male-specific therapeutic strategy for Alzheimers disease. Significance StatementThe molecular basis of sex differences in Alzheimers disease vulnerability remains unresolved. We show that mGluR5 functions as a male-specific co-receptor for pathogenic A{beta}42/PrPC signaling and identify the E3 ubiquitin ligase TRIM9 as the factor governing this dimorphism. TRIM9 selectively assembles the A{beta}42/PrPC/mGluR5 complex in male brain, and its genetic deletion disrupts complex formation while restoring Akt/GSK3{beta}-dependent autophagic clearance of amyloid. These findings define a sex-specific signaling axis underlying {beta}-amyloid pathogenesis and establish TRIM9 as a candidate target for sex-informed Alzheimers therapeutics.

neuroscience↗

bioRxiv2025

Structural bases for Nuclear Factor 1-X activation and DNA recognition. Prototypic insight into the NFI transcription factor family

Nuclear Factor I (NFI) proteins were first identified in adenovirus DNA replication and later as regulators of gene transcription, stem cell proliferation, and differentiation. They play key roles in development, cancer and congenital disorders. Within the NFI family, NFI-X is critical for neural stem cell biology, hematopoiesis, muscle development, muscular dystrophies and oncogenesis. Here, we present the first structural characterization of the NFI transcription factor, NFI-X, both alone and bound to its consensus palindromic DNA site. Our analyses reveal a novel, MH1-like fold within NFI-X DNA-binding domain (DBD) and identify crucial structural determinants for activity, such as a Zn{superscript 2} binding site, dimeric assembly, activation mechanism and DNA-binding specificity. Given the >95% sequence identity within the NFI DBDs, our structural data are prototypic for the entire family; a NFI Rosetta Stone that allows decoding a wealth of biochemical and functional data and provides a precise target for drug design in a wider disease context.

biochemistry↗

bioRxiv2024

Systemic inflammation triggers long-lasting neuroinflammation and accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha-synuclein

Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinsons disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human -synuclein (Snca+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca+/+ rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes. However, only LPS Snca+/+ rats showed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction in the release of evoked dopamine in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby -synuclein and inflammation interact to promote neurodegeneration in PD.

neuroscience↗

bioRxiv2023

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Immunometabolism investigates the complex interplay between the immune system and cellular metabolism. This study highlights the effects of mitochondrial frataxin (FXN) depletion, which causes Friedreichs ataxia (FRDA), a neurodegenerative condition characterized by coordination and muscle control deficiencies. Using single-cell RNA sequencing, we identified specific cell groups in the cerebellum of a FRDA mouse model, emphasizing a notable inflammatory microglial response. These FXN-deficient microglia cells exhibited enhanced inflammatory reactions. Furthermore, our metabolomic analyses revealed increased glycolysis and itaconate production in these cells, possibly driving the inflammation. Remarkably, butyrate treatment counteracted these immunometabolic changes, triggered an antioxidant response via the itaconate-Nrf2-GSH pathways, and dampened inflammation. The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.

physiology↗

bioRxiv2021

An untargeted metabolomic approach to identify antiviral defense mechanisms in memory leukocytes secreting in vitro IgG anti-SARS-Cov-2

Available knowledge shows that individuals infected by SARS-CoV-2 undergo an altered metabolic state in multiple organs. Metabolic activities are directly involved in modulating the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism relates with inflammatory responses. To better elucidate the underlying biochemistry of leukocytes response, we focused our analysis on the possible relationships between SARS-CoV-2 post-infection stages and distinct metabolic pathways. Indeed, in cultures of peripheral blood mononuclear cells (PBMC, n=48) obtained 60-90 days after infection and showing in vitro IgG antibody memory for spike-S1 antigen (n=19), we observed a significant altered metabolism of tryptophan and urea cycle pathways. This work for the first time identifies metabolic routes in cell metabolism possibly related to later stages of immune defense against SARS-Cov-2 infection, namely when circulating antibodies may be absent, but an antibody memory is present. The results suggest a reprogramming of leukocyte metabolism after viral pathogenesis through activation of specific amino acid pathways possibly related to protective immunity against SARS-CoV-2.

cell biology↗

bioRxiv2021

An altered metabolism in leukocytes showing in vitro igG memory from SARS-CoV-2-infected patients

Coronavirus disease 2019 (COVID 19) is a systemic infection that exerts a significant impact on cell metabolism. In this study we performed metabolomic profiling coupled with multivariate statistics analysis obtained from 43 in vitro cultures of peripheral blood mononuclear cells (PBMC), 19 of which displaying IgG memory for spike-S1 antigen 60-90 days after infection. By using mass spectrometry analysis, a significant up regulation of S-adenosyl-Homocysteine, Sarcosine and Arginine was found in leukocytes showing IgG memory. These metabolites are known to be involved in physiological recovering from viral infections and immune activities, and our findings might represent a novel and easy measure that could be of help in understanding SARS-Cov-2 effects on leukocytes.

cell biology↗