Biology subjects

Geraets, J. A.

Publications and source records attributed to Geraets, J. A..

3 recordsLinked to original sources

bioRxiv2022

The 3D structure of lipidic fibrils of α-synuclein

-synuclein (Syn) is abundant in neurons, but its misfolding and abnormal fibrillization are associated with severe neurodegenerative diseases. Although interactions between Syn and phospholipid membranes are relevant during Syn fibril assembly, insights into the interactions of Syn fibrils with phospholipids have remained elusive. Here, we present six novel polymorphic atomic structures of Syn fibrils aggregated in the presence of phospholipids. The structures reveal that phospholipids favor a novel protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities between the protofilaments. These findings provide a structural rationale for fibril-induced lipid extraction, a mechanism likely to be involved in the development of -synucleinopathies.

molecular biology↗

bioRxiv2021

α-Synuclein polymorphism determines oligodendroglial dysfunction

Synucleinopathies, such as Parkinsons disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases. For both PD and MSA, -synuclein fibril inclusions inside brain cells are neuropathological hallmarks. In addition, amplification of -synuclein fibrils from body fluids is a potential biomarker distinguishing PD from MSA. However, little is known about the structure of -synuclein fibrils amplified from human samples and its connection to -synuclein fibril structure in the human brain. Here we amplified -synuclein fibrils from PD and MSA brain tissue, characterized its seeding potential in oligodendroglia, and determined the 3D structures by cryo-electron microscopy. We show that the -synuclein fibrils from a MSA patient are more potent in recruiting the endogenous -synuclein and evoking a redistribution of TPPP/p25 protein in mouse primary oligoden-droglial cultures compared to those amplified from a PD patient. Cryo-electron microscopy shows that the PD- and MSA-amplified -synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface. The structures of the brain-tissue amplified -synuclein fibrils are also similar to other in vitro and ex vivo -synuclein fibrils. Together with published data, our results suggest that Syn fibrils differ between PD and MSA in their quaternary arrangement and could further vary between different forms of PD and MSA.

neuroscience↗

bioRxiv2018

2.8 A resolution cryo-EM structure of human parechovirus 3 in complex with Fab from a neutralizing antibody

Human parechovirus 3 (HPeV3) infection is associated with sepsis in neonates characterized by significant immune activation and subsequent tissue damage. Strategies to limit infection have been unsuccessful due to inadequate molecular diagnostic tools for early detection and lack of a vaccine or specific antiviral therapy. Towards the latter, we present a 2.8 [A]-resolution structure of HPeV3 in complex with fragments from a neutralizing human monoclonal antibody AT12-015 using cryo-EM and image reconstruction. Modeling revealed that the epitope extends across neighboring asymmetric units with contributions from capsid proteins VP0, VP1, and VP3. Antibody decoration was found to block binding of HPeV3 to cultured cells. Additionally at high-resolution, it was possible to model a stretch of RNA inside the virion and from this identify the key features that drive and stabilize protein-RNA association during assembly.\n\nImportance\n\nHPeV3 is receiving increasing attention as a prevalent cause of sepsis-like symptoms in neonates, which despite the severity of disease, there are no effective treatments available. Structural and molecular insights into virus neutralization are urgently needed, especially as clinical cases are on the rise. Towards this goal, we present the first structure of HPeV3 in complex with fragments from a neutralizing monoclonal antibody. At high-resolution it was possible to precisely define the epitope that when targeted, prevents virions from binding to cells. Such an atomic-level description is useful for understanding host-pathogen interaction, viral pathogenesis mechanisms, and for finding potential cures for infection and disease.

microbiology↗