Biology subjects

Korobeinikov, A.

Publications and source records attributed to Korobeinikov, A..

4 recordsLinked to original sources

bioRxiv2026

Reverse engineering Lewy bodies suggests alpha-synuclein pathology as condensatopathy

Understanding how soluble monomeric alpha-synuclein transitions into pathological alpha-synuclein (Lewy bodies) has remained a central challenge in neurodegeneration. Existing models, largely based on treating cells and animals with pre-formed alpha-synuclein fibrils cannot account for the emergence of the first inclusion without pre-existing seeds. Here, we combine in vitro reconstitutions, computational modeling and a minimal cellular system to show that phase separation of alpha-synuclein with an interacting scaffold can recapitulate Lewy body-like structures. An unbiased proteomics screen, live-cell imaging, correlative light-electron microscopy, and soft X-ray tomography show that Lewy body-like structures are associated with redistribution of actin and membrane-bound organelles, with mitochondria accumulating at their periphery in an actin-dependent manner. Structural analyses further indicate that alpha-synuclein condensates provide local environments in which the insoluble beta-sheets can form. Together, these findings support a seed-independent trajectory from soluble alpha-synuclein through condensation and progressive immobilization to Lewy body-like assemblies and, subsequently, insoluble beta-sheet fibrils. This framework offers a new mechanistic route for understanding the disease progression and promises to guide the design of innovative therapeutic interventions.

neuroscience↗

bioRxiv2026

Synapsin-1 and actin form ordered nanoscale assemblies

Liquid-liquid phase separation is a vital and ubiquitous principle of subcellular organization. Several actin-binding proteins have recently been shown to undergo liquid-liquid phase separation, forming micron-sized droplets that assemble actin into distinct network shapes. However, our knowledge of how these phase-separated proteins organize actin filaments at the nanoscale is rather limited. Here, we seek to address this knowledge gap by investigating synapsin-1 condensates through a combination of computational simulations and nanoscale imaging experiments. Our results show that while synapsin-1 condensates by themselves lack any special structural organization, the addition of actin filaments results in the generation of a regularly organized actin scaffold within the condensates. The organized scaffold forms both when actin and synapsin-1 are added simultaneously and when actin is added after the formation of synapsin condensates. Dissolving the condensates, by synapsin-1 removal, leaves the actin scaffold largely unaffected in both simulations and experiments, implying that this scaffold should guide droplet reformation when synapsin-1 is added back. Taken together, our findings suggest that the actin-rich component of the condensate retains a structural memory that promotes and guides the reassembly of synapsin-actin condensates. This structural memory may be important in the long-term maintenance of synaptic function in vivo.

biophysics↗

bioRxiv2025

Brain-derived synaptic vesicles have an intrinsic ability to sequester tubulin

The presence and function of microtubules within the synaptic bouton has long been under investigation. In recent years evidence has accumulated that connects the synaptic vesicle cluster to the local dynamics of microtubule ends. Nonetheless, one question remains open, namely whether the vesicles influence the availability of tubulin within the synaptic compartment. An analysis of previously published live imaging experiments indicates that tubulin is strongly enriched in the synaptic vesicle cluster. To analyze the vesicle-tubulin interaction directly, we isolated vesicles from the mouse brain and imaged them together with fluorescent tubulin in vitro. We found that soluble tubulin is collected by synaptic vesicles in physiological buffers, resulting in the formation of tubulin-rich regions (TRRs) on the respective vesicle clusters. We conclude that the synaptic vesicle cluster is indeed able to recruit soluble tubulin.

neuroscience↗

bioRxiv2024

CONDENSATES OF SYNAPTIC VESICLES AND SYNAPSIN ARE MOLECULAR BEACONS FOR ACTIN SEQUESTERING AND POLYMERIZATION

Neuronal communication relies on precisely maintained synaptic vesicle (SV) clusters, which assemble via liquid-liquid phase separation (LLPS). This process requires synapsins, the major synaptic phosphoproteins, which are known to bind actin. The reorganization of SVs, synapsins and actin is a hallmark of synaptic activity, but their interplay is still unclear. Here, we combined the reconstitution approaches, expansion microscopy, super-resolution imaging and cryo-electron tomography to dissect the roles of synapsin-SV condensates in the organization of the presynaptic actin cytoskeleton. Our data indicate that LLPS of synapsin initiates actin polymerization, allowing for SV:synapsin:actin assemblies to facilitate the mesoscale organization of SV clusters along axons mimicking the native presynaptic organization in both lamprey and mammalian synapses. Understanding the relationship between the actin network and synapsin-SVs condensates is an essential building block on a roadmap to unravel how coordinated neurotransmission along the axon enables circuit function and behavior.

cell biology↗