Biology subjects

Tiberi, C.

Publications and source records attributed to Tiberi, C..

3 recordsLinked to original sources

bioRxiv2025

Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies

The aggregation of the protein alpha-synuclein (Syn) is a common feature of multiple neurodegenerative diseases collectively called synucleinopathies, for which the pathobiology is not well understood. The different phenotypic characteristics of the synucleinopathies Parkinsons disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by Syn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within neuronal cells and directly in native patient brain homogenates, we show that pathogenic Syn from distinct synucleinopathies (PD, DLB and MSA) are structurally different. Further, we found that fibrillar structural differences are associated with different fibril interactomes and neuronal responses. We discovered disease-specific ubiquitination patterns and turnover profiles for pathogenic Syn species, detected molecular pathways responding specifically to the uptake of different Syn fibrillar polymorphs, and identified a subset of the involved proteins as candidate direct interactors of Syn. In particular, components of the Ubiquitin-proteasomal System (UPS), including E3 ubiquitin ligases, chaperones, and Deubiquitinating proteins, showed disease/polymorph-specific interaction patterns, possibly accounting for different resistance of patient-derived Syn fibrils to degradation. Genetic modulation with CRISPR-based tools showed that members of the UPS degradation pathway (three E3 ligases: UBE3A, TRIM25, HUWE1 and the AAA+ ATPase VCP) reduced Syn inclusions, in a strain-specific manner. LiP-MS also identified sets of proteins with altered protease susceptibility in postmortem brain homogenates of PD, DLB, and MSA patients. These sets were largely disease-specific and included proteins altered in cells treated with fibrils derived from patients with the matching disease. Our findings provide insight into cellular processes involved in the accumulation and turnover of Syn pathogenic aggregates in PD, DLB and MSA in a disease specific manner and constitutes a resource of potential novel drug targets in these synucleinopathies.

systems biology↗

bioRxiv2025

Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles

-synuclein (-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinsons disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between -syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined cells exposed to -syn fibrils vs control cells with a focus on mitochondria. We found that upon exposure to -syn fibrils, mitochondria increase in size, cristae structure gets defects, and mitochondria enhance the budding of mitochondrial-derived vesicles (MDVs). MDV formation reflects an evolutionarily conserved mechanism reminiscent of bacterial outer membrane vesicle (OMV) biogenesis. Structural proteomics analysis by mass spectrometry corroborates this microscopy observation by identifying changes in multiple proteins that regulate cristae structure, MDV formation, and trafficking. Our results provide a new link between -syn and mitochondria and identify novel pathways responding to -syn aggregates, particularly that -synuclein directly triggers MDV generation. The processes we detected could be of interest for diagnostics and potential therapeutic interventions.

neuroscience↗

bioRxiv2021

East-African savanna dynamics: from a knowledge-based model to the possible futures of a social-ecological system

Sub-Saharan savanna ecosystems are undergoing transitions such as bush encroachment, desertification or agricultural expansion. Such shifts and persistence of land cover are increasingly well understood, especially bush encroachment which is of major concern in pastoral systems. Although dominant factors can explain such transformations, they often result from intertwined causes in which human activities play a significant role. Therefore, in this latter case, these issues may require integrated solutions, involving many interacting components. Ecosystem modelling has proved appropriate to support decision-makers in such complex situations. However, ecosystem models often require lots of quantitative information for estimating parameters and the precise functional form of interactions is often unknown. Alternatively, in rangeland management, States-and-Transitions Models (STMs) have been developed to organize knowledge about system transitions and to help decision-makers. However, these conceptual diagrams often lack mathematical analyzing tools, which strongly constrains their complexity. In this paper, we introduce the Ecological Discrete-Event Network (EDEN) modelling approach for representing the qualitative dynamics of an East-African savanna as a set of discrete states and transitions generated from empirical rules. These rules are derived from local knowledge, field observations and scientific literature. In contrast with STMs, EDEN generates automatically every possible states and transitions, thus enabling the prediction of novel ecosystem structures. Our results show that the savanna is potentially resilient to the disturbances considered. Moreover, the model highlights all transitions between vegetation types and socio-economic profiles under various climatic scenarios. The model also suggests that wildlife diversity may increase socio-economic resistance to seasonal drought. Tree-grass coexistence and agropastoralism have the widest ranges of conditions of existence of all vegetation types and socio-economic profiles, respectively. As this is a preliminary use of EDEN for applied purpose, analysis tools should be improved to enable finer investigation of desirable trajectories. By translating local knowledge into ecosystem dynamics, the EDEN approach seems promising to build a new bridge between managers and modellers.

ecology↗