Biology subjects

Sokratian, A.

Publications and source records attributed to Sokratian, A..

4 recordsLinked to original sources

bioRxiv2024

Mouse α-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases

Short AbstractThe intricate process of -synuclein aggregation and fibrillization hold pivotal roles in Parkinsons disease (PD) and multiple system atrophy (MSA). While mouse -synuclein can fibrillize in vitro, whether these fibrils commonly used in research to induce this process or form can reproduce structures in the human brain remains unknown. Here we report the first atomic structure of mouse -synuclein fibrils, which was solved in parallel by two independent teams. The structure shows striking similarity to MSA-amplified and PD-associated E46K fibrils. However, mouse -synuclein fibrils display altered packing arrangements, reduced hydrophobicity, heightened fragmentation sensitivity, and evoke only weak immunological responses. Furthermore, mouse -synuclein fibrils exhibit exacerbated pathological spread in neurons and humanized -synuclein mice. These findings provide new insights into the structural underpinnings of -synuclein pathogenicity and emphasize a need to reassess the role of mouse -synuclein fibrils in the development of related diagnostic probes and therapeutic interventions.

neuroscience↗

bioRxiv2023

Gut mucosal cells transfer α-synuclein to the vagus nerve

Epidemiological and histopathological findings have raised the possibility that misfolded -synuclein protein might spread from the gut to the brain and increase the risk of Parkinsons disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant -synuclein fibrils to study gut to brain -synuclein transfer, the possible origins of misfolded -synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express -synuclein. In this study, we employed mouse intestinal organoids expressing human -synuclein to observe the transfer of -synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of -synuclein expression. In intact mice that express pathological human -synuclein, but no mouse -synuclein, -synuclein fibril templating activity emerges in -synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human -synuclein expression to intestinal epithelial cells, -synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of -synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of -synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar -synuclein protein that might arise in gut mucosal cells.

neuroscience↗

bioRxiv2022

Structural and functional landscape of α-synuclein fibril conformations amplified from cerebrospinal fluid

Lewy body dementias are pathologically defined by the deposition of -synuclein fibrils into inclusions throughout the brain. Cerebrospinal fluid(CSF) in disease harbors circulating -synuclein-fibril seeds, and parental -synuclein fibrils can template core structure into amplified fibrils. Using cryo-electron microscopy, we identify six novel -synuclein fibril assemblies amplified from ten CSF samples (3.8[A] to 2.9[A] nominal resolutions). Fibrils are classified based on two types of filament interaction, two types of {beta}-sheet stacking, and two types of hydrophobic pocket. CSF-amplified fibril products have one, two, or three distinct assemblies each. Six of ten samples share a common fibril assembly. Within this classification, the fibrils have distinct profiles in amyloid dye binding, and dramatically different potencies in both seeding new inclusions in neurons and evoked microglial pro-inflammatory responses. However, no single structural feature predicts functional phenotypes. Our results highlight CSF as a valuable resource to identify novel -synuclein assemblies potentially important in disease.

neuroscience↗

bioRxiv2020

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinsons disease (PD). The link between LRRK2 and -synuclein aggregation in PD remains enigmatic. Numerous reports suggest critical LRRK2 functions in microglial responses. Herein, we find that LRRK2-positive immune cells in the brain represent CD68-positive pro-inflammatory, monocyte-derived macrophages, distinct from microglia. Rod -synuclein fibrils stimulate LRRK2 kinase activity in monocyte-derived macrophages, and LRRK2 mutations lead to enhanced recruitment of classical monocytes into the midbrain in response to -synuclein. LRRK2 kinase inhibition blocks -synuclein fibril induction of LRRK2 protein in both human and murine macrophages, with human cells demonstrating much higher LRRK2 levels and kinase activity than equivalent murine cells. Further, interferon-{gamma} strongly induces LRRK2 kinase activity in primary human macrophages in comparison to weak effects observed in murine cells. These results highlight peripheral immune responses in LRRK2-linked paradigms that further connect two central proteins in PD.

neuroscience↗