Biology subjects

Zachrdla, M.

Publications and source records attributed to Zachrdla, M..

3 recordsLinked to original sources

bioRxiv2025

Human- and Rodent-derived Extracellular Vesicles Mediate the Spread of Pathology in MSA-like Models

Multiple system atrophy (MSA) is characterized by the presence of protein-rich inclusions mainly within oligodendrocytes, comprised primarily by the neuronal protein Synuclein and the oligodendroglial-specific phosphoprotein TPPP/p25. Mature oligodendrocytes do not normally express detectable Synuclein levels, suggesting that its oligodendroglial accumulation may arise from intercellular transfer, potentially via extracellular vesicles (EVs); however the precise role of oligodendroglial-derived EVs in MSA progression remains relatively understudied. Herein, we characterized the cargo/features and pathogenic potential of EVs released by oligodendrocytes treated with human Synuclein fibrils amplified from MSA or Parkinsons disease patient brains (or human recombinant Synuclein fibrils) and EVs isolated from murine and human MSA (or respective control) brains. Our findings reveal that both oligodendroglial cell- and brain-derived EVs harbor pathological Synuclein and TPPP/p25 conformations, similar to those accumulating in human MSA brains. These EVs are readily taken up by both neurons and oligodendrocytes, driving Synuclein propagation in vitro. Importantly, inoculation of these MSA-like EVs in animal models induce robust pSer129-Synuclein accumulation along the nigrostriatal axis, colocalizing with markers of mature oligodendrocytes and dopaminergic neurons. These findings underscore the pivotal role of oligodendroglial-derived EVs in pathology progression and neuronal-oligodendroglial communication, positioning them as promising targets for therapeutic strategies aimed at combating alpha-Synucleinopathies.

neuroscience↗

bioRxiv2023

GSK3β phosphorylation catalyzes the aggregation of Tau into Alzheimer's disease-like amyloid strain

The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown. Here we show that the serine/threonine kinase GSK3{beta} catalyzes the aggregation of the protein tau into an Alzheimers disease-like amyloid strain. We demonstrate that phosphorylation by GSK3{beta}, but not by several other kinases, promotes the aggregation of full-length tau through enhanced phase separation into gel-like condensate structures. Cryo-electron microscopy further reveals that the amyloid fibrils formed by GSK3{beta}-phosphorylated tau adopt a fold comparable to that of paired helical filaments isolated from the brains of AD patients. Our results elucidate the intricate relationship between post-translational modification and the formation of tau strains in neurodegenerative diseases.

biophysics↗

bioRxiv2022

Contributions of the N-terminal intrinsically disordered region of the SARS-CoV-2 nucleocapsid protein to RNA-induced phase separation

SARS-CoV-2 nucleocapsid protein is an essential structural component of mature virions, encapsulating the genomic RNA and modulating RNA transcription and replication. Several of its activities might be associated with the proteins ability to undergo liquid-liquid phase separation. NSARS-CoV-2 contains an intrinsically disordered region at its N-terminus (NTE) that can be phosphorylated and is affected by disease-relevant mutations. Here we show that NTE deletion decreases the range of RNA concentrations that can induce phase separation of NSARS-CoV-2. In addition, deletion of the prion-like NTE allows NSARS-CoV-2 droplets to retain their liquid-like nature during incubation. We further demonstrate that RNA-binding engages multiple parts of the NTE and changes NTEs structural properties. The results form the foundation to characterize the impact of N-terminal mutations and post-translational modifications on the molecular properties of the SARS-CoV-2 nucleocapsid protein. StatementThe nucleocapsid protein of SARS-CoV-2 plays an important role in both genome packaging and viral replication upon host infection. Replication has been associated with RNA-induced liquid-liquid phase separation of the nucleocapsid protein. We present insights into the role of the N-terminal part of the nucleocapsid protein in the proteins RNA-mediated liquid-liquid phase separation.

biophysics↗