Biology subjects

Mauri, P.

Publications and source records attributed to Mauri, P..

7 recordsLinked to original sources

bioRxiv2024

CoPPIs Algorithm: A Tool to Unravel Protein Cooperative Strategies in Pathophysiological Conditions

We present here the Co-expressed Protein-Protein Interactions (CoPPIs) algorithm. In addition to minimizing correlation-causality imbalance and contextualizing PPIs to the investigated systems, it combines PPIs and protein co-expression networks to identify differentially correlated functional modules. To test CoPPIs, we processed a set of proteomic profiles from different brain areas of controls and subjects affected by idiopathic Parkinsons disease or carrying a GBA1 mutation. Its robustness was supported by the extraction of functional modules, related to translation and mitochondria, whose involvement in PD pathogenesis is well documented. Furthermore, the selection of hubs and bottlenecks from the weighted PPI networks provided molecular clues consistent with the PD pathophysiology. Of note, like quantification, the CoPPIs algorithm revealed less variations when comparing disease groups than when comparing diseased and controls. However, correlation and quantification results showed low overlap, suggesting the complementarity of these measures. An observation that opens the way to a new investigation strategy that takes into account not only protein expression, but also the level of coordination among proteins that cooperate to perform a given function.

systems biology↗

bioRxiv2024

A system biology-oriented investigation of Arabidopsis proteomes altered in chloroplast biogenesis and retrograde signaling reveals adaptive responses at whole cell level.

Communication across different plant cell compartments relies on an intricate network of molecular interactions, required for the orchestration of organelle development and adaptation to the environment. In this scenario, the Pentatricopeptide Repeat (PPR) Protein GENOMES UNCOUPLED1 (GUN1) plays a key role in transferring information from both developing and mature chloroplasts to the nucleus with the aim to coordinate gene expression between the two genomes. However, its role and the related signaling molecules are still under debate. To help shed light on this matter, we attempted the holistic description of Arabidopsis thaliana proteome upon perturbation of chloroplast biogenesis by lincomycin (Lin), in a genetic context devoid of GUN1-dependent plastid-to-nucleus signaling pathway. Furthermore, the topological analysis of protein-protein interaction (PPI) and protein co-expression networks allowed the identification of protein hubs/bottlenecks characterizing genotypes and conditions, such as proteases, HSPs/Chaperones and redox proteins. Taken together, our findings indicate that GUN1 is required to orchestrate a plastid-located response to plastid protein synthesis inhibition while, in its absence, the reorganization of the activities associated with extra-plastid compartments, such as cytosol, vacuole and mitochondria, prevails. From this landscape, we documented a new role of the Oxygen Evolving Complex subunit PsbO, which appears to be an unconventional photosynthetic protein, as it accumulates in non-photosynthetic plastids and plays a central role in promoting chloroplast breakdown when plastid functions are altered.

systems biology↗

bioRxiv2023

WOMBAT-P: Benchmarking Label-Free Proteomics Data Analysis Workflows

Proteomics research encompasses a wide array of experimental designs, resulting in diverse datasets varying in structure and properties. This diversity has led to a considerable variety of software solutions for data analysis, each of them using multiple tools with different algorithms for operations like peptide-spectrum matching, protein inference, quantification, statistical analysis, and visualization. Computational workflows combine these algorithms to facilitate end-to-end analysis, spanning from raw data to detecting differentially regulated proteins. We introduce WOMBAT-P, a versatile platform designed for the automatic benchmarking and comparison of bottom-up label-free proteomics workflows. By standardizing software parameterization and workflow outputs, WOMBAT-P empowers an objective comparison of four commonly utilized data analysis workflows. Furthermore, WOMBAT-P streamlines the processing of public data based on the provided metadata, with an optional specification of 30 parameters. Wombat-P can use Sample and Data Relationship Format for Proteomics (SDRF-Proteomics) as the file input to simply process annotated local or ProteomeXchange deposited datasets. This feature offers a shortcut for data analysis and facilitates comparisons among diverse outputs. Through an examination of experimental ground truth data and a realistic biological dataset, we unveil significant disparities and a low overlap between identified and quantified proteins. WOMBAT-P not only enables rapid execution and seamless comparison of four workflows (on the same dataset) using a wide range of benchmarking metrics but also provides insights into the capabilities of different software solutions. These metrics support researchers in selecting the most suitable workflow for their specific dataset. The modular architecture of WOMBAT-P promotes extensibility and customization, making it an ideal platform for testing newly developed software tools within a realistic data analysis context.

bioinformatics↗

bioRxiv2022

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by mutations in the WFS1 gene leading to a wide spectrum of clinical dysfunctions, among which blindness, diabetes and neurological deficits are the most prominent. WFS1 encodes for the endoplasmic reticulum (ER) resident transmembrane protein Wolframin with multiple functions in ER processes. However, the WFS1-dependent etiopathology in retinal cells is unknown. Herein, we showed that Wfs1 mutant mice developed early retinal electrophysiological impairments followed by marked visual loss. Interestingly, axons and myelin disruption in the optic nerve preceded the degeneration of the retinal ganglion cell bodies in the retina. Transcriptomics at pre-degenerative stage revealed the STAT3-dependent activation of proinflammatory glial markers with reduction of the homeostatic and pro-survival factors Glutamine synthetase and BDNF. Furthermore, label-free comparative proteomics identified a significant reduction of the monocarboxylate transport isoform 1 (MCT1) and its partner Basigin that are highly enriched on retinal astrocytes and myelin-forming oligodendrocytes in optic nerve together with Wolframin. Loss of MCT1 caused a failure in lactate transfer from glial to neuronal cell bodies and axons leading to a chronic hypometabolic state. Thus, this bioenergetic impairment is occurring concurrently both in the axonal regions and cell bodies of the retinal ganglion cells, selectively endangering their survival while impacting less on other retinal cells. This metabolic dysfunction occurs months before the frank RGC degeneration suggesting an extended time window for intervening with new therapeutic strategies focused on boosting retinal and optic nerve bioenergetics in WS1.

neuroscience↗

bioRxiv2021

Enrichment analysis of GWAS data in autoimmunity delineates the multiple sclerosis-Epstein Barr virus association

We exploited genetic information to assess non-genetic influences in autoimmunity. We isolated gene modules whose products physically interact with environmental exposures related to autoimmunity, and analyzed their nominal statistical evidence of association with autoimmune and non-autoimmune diseases in genome-wide association studies (GWAS) data. Epstein Barr virus (EBV) and other Herpesviruses interactomes emerged as specifically associated with multiple sclerosis (MS), possibly under common regulatory mechanisms. Analyses of MS blood and brain transcriptomes, cytofluorimetric studies of endogenous EBV-infected lymphoblastoid lines, and lesion immunohistochemistry, confirmed a dysregulation of MS-associated EBV interactors, suggesting their contribution to CD40 signaling alterations in MS. These interactors resulted enriched in modules from inherited axonopathies-causing genes, supporting a link between EBV and neurodegeneration in MS, in accord with the observed transcriptomic dysregulations in MS brains. They were also enriched with top-ranked pharmaceutical targets prioritized on a genetic basis. This study delineates a disease-specific influence of herpesviruses on MS biology.

neuroscience↗

bioRxiv2019

Gcn5 and Ubp8 dependent ubiquitylation affects glycolysis in yeast

Many of the molecular mechanisms affected by ubiquitylation are highly conserved from yeast to humans and are associated to a plethora of diseases including cancers. To elucidate the regulatory role of epigenetic factors such as the catalytic subunits of SAGA complex, KAT-Gcn5 and Ub-protease Ubp8, on ubiquitylation of non-histone proteins we have performed a comprehensive analysis of the Ub-proteome in yeast Saccharomyces cerevisiae in strains disrupted in Gcn5, Ubp8 or both respect to wild type. We found significative alteration of ubiquitylation in proteins belonging to different functional categories with a recurrence of identical proteins in absence of Gcn5 or Ubp8 indicating shared targets and their interlaced function. Among the processes involved we noteworthy identified all major enzymes engaged in energy metabolism and glycolysis such as PFK1, PFK2 and others showing increased ubiquitylation respect to WT. We showed that the higher degree of ubiquitylation found is at post-translational level and does not depend on transcription. Noteworthy, we found in vivo severe defects of growth in poor sugar medium and inability to adaptive switch from fermentative to respiratory growth in strains lacking Gcn5 and Ubp8. Our findings data provide a novel, direct link, between metabolism and epigenetic control with a novel role of DUB-Ubp8 and KAT-Gcn5 on the ubiquitylation marking all the main glycolytic enzymes required for an effective execution of the glycolytic flux. Collectively our experimental results and the proposed model can lead to future research and innovative strategies that by targeting epigenetic modulators might be able to lower sugar utilization also in human cells.\n\nAuthor SummaryMolecular mechanisms dissected in simple yeast might be translated to similar circuitries in human cells for new discoveries in human diseases including cancer. Ubiquitylation of proteins is an evolutionary conserved mechanism required for many biological processes. Different post-translational modifications (PTMs) such as ubiquitylation, acetylation, methylation etc. are reciprocally regulated for deposition or removal. Epigenetic factors writing the PTMs code are often components of multiproteic complexes such as SAGA complex that holds the K-acetyltransferase (KAT) Gcn5 and the Ubiquitin-protease (DUB) Ubp8 highly conserved in Evolution. Cells respond to environment and nutrients by changing metabolism and group of enzymes involved in specific pathways are often coregulated by the deposition of selected PTMs. This study analyses the composition and quantitation of Ub-proteins differentially modified in absence of KAT-Gcn5 and DUB-Ubp8 in yeast. Interstingly, we highlighted the role of Gcn5/Ubp8 dependent ubiquitylation in marking major glycolytic enzymes necessary for glucose utilization. Our study suggests a novel regulatory pathway and, considering that lowering glycolysis is a promising strategy to target tumor metabolism, we propose this study as an interesting perspective to lower enhanced glycolysis in tumors.

molecular biology↗

bioRxiv2018

Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain (AL) amyloidosis patient

Systemic light chain (AL) amyloidosis is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 [A] resolution cryo-electron microscopy (cryo-EM) map and structural model of amyloid fibrils extracted from the heart of an AL patient affected by severe amyloid cardiomyopathy. The fibrils are composed of one asymmetric protofilament, showing typical 4.9 [A] stacking and parallel cross-{beta} architecture. Two distinct polypeptide stretches belonging to the LC variable domain (Vl) could be modelled in the density (total of 77 residues), stressing the role of the Vl domain in fibril assembly and LC aggregation. Despite high levels of Vl sequence variability, residues stabilising the observed fibril core are conserved through several Vl domains, highlighting structural motifs that may be common to misfolded LCs. Our data shed first light on the architecture of life-threatening LC amyloid deposits, and provide a rationale for correlating LC amino acid sequences and fibril structures.

biochemistry↗