Biology subjects

Izzi, F.

Publications and source records attributed to Izzi, F..

3 recordsLinked to original sources

bioRxiv2024

Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes

Leucine-rich repeat kinase 2 (LRRK2) not only plays a vital role in familial forms of Parkinsons disease (PD) but also represents a risk factor for idiopathic PD. Its multi-domain architecture enables fine-tuned regulation of its biological function by orchestrating intra- and intermolecular interactions. Here, we present BioID proximity proteomes of LRRK2 that reveal new interactors, which we further characterize using a novel evolutionary and structural bioinformatics pipeline. Co-evolutionary analysis of the protein-protein interaction network identifies a structural and functional module enriched in cytoskeletal components associated with the centrosome and microtubules. In addition, structural modelling of binary interactions using AlphaFold-Multimer reveals distinct groups of interactors that engage LRRK2 in a manner dependent on specific conformations and epitopes. Furthermore, we identify distinct changes in the LRRK2 proximity proteome that are induced by the type I kinase inhibitor MLi-2 or by co-expression of the LRRK2 upstream effector RAB29. Depending on its activity state and conformation, these protein-protein interactions link LRRK2 to defined cellular sub-compartments, including centriolar satellites and vesicular sub-compartments. SummaryThis study defines a comprehensive, LRRK2 interaction network by combining proximity proteomics with evolutionary and structural analyses, revealing how LRRK2 conformation and activity state dictate distinct protein-protein interactions. These findings link LRRK2 to conserved centrosomal, cytoskeletal, and vesicular pathways, providing mechanistic insight into its role in Parkinsons disease. Key resultsO_LICentrosome-linked LRRK2 network: BioID combined with co-evolutionary analysis identifies a highly conserved module enriched in centrosomal and microtubule-associated proteins, including CYLD as a top co-evolved interactor. C_LIO_LIConformation-specific interactions: AlphaFold-Multimer modelling reveals distinct classes of LRRK2 interactors that bind different domains and conformations ("locked" vs. "unlocked"), corresponding to specific cellular functions. C_LIO_LIState-dependent rewiring of the interactome: The type I inhibitor MLi-2 selectively redirects LRRK2 to centriolar satellite proteins, whereas RAB29 co-expression shifts LRRK2 interactions toward vesicular and lysosomal pathways. C_LI

neuroscience↗

bioRxiv2023

Muscle Preflex Response to Perturbations in locomotion: In-vitro experiments and simulations with realistic boundary conditions

1Neuromuscular control loops feature substantial communication delays, but mammals run robustly even in the most adverse conditions. In-vivo experiments and computer simulation results suggest that muscles preflex--an immediate mechanical response to a perturbation--could be the critical contributor. Muscle preflexes act within a few milliseconds, an order of magnitude faster than neural reflexes. Their short-lasting activity makes mechanical preflexes hard to quantify in-vivo. Muscle models, on the other hand, require further improvement of their prediction accuracy during the non-standard conditions of perturbed locomotion. Additionally, muscles mechanically adapt by increased damping force. Our study aims to quantify the mechanical preflex work and test its mechanical force adaptation. We performed in-vitro experiments with biological muscle fibers under physiological boundary conditions, which we determined in computer simulations of perturbed hopping. Our findings show that muscles initially resist impacts with a stereotypical stiffness response--identified as short-range stiffness--regardless of the exact perturbation condition. We then observe a velocity adaptation to the force related to the amount of perturbation. The main contributor to the preflex work adaptation is not the force difference but the muscle fiber stretch difference. We find that both muscle stiffness and damping are activity-dependent properties. These results indicate that neural control could tune the preflex properties of muscles in expectation of ground conditions leading to previously inexplicable neuromuscular adaptation speeds.

physiology↗

bioRxiv2021

Comparative transcriptional analysis of the satellite glial cell injury response

Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. The SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNAseq technologies has enabled a new approach to investigate SGCs. Here we publish a dataset from mice subjected to sciatic nerve injury as well as a dataset from dorsal root ganglia cells after 3 days in culture. We use a meta-analysis approach to compare the injury response with that in other published datasets and conclude that SGCs share a common signature following sciatic nerve crush and sciatic ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state, while others start resembling Schwann cell-like precursors. The datasets are available via the Broad Institute Single Cell Portal.

neuroscience↗