Objective: To understand the extracellular space (ECS) diffusion in synucleinopathy.

Background: The pathogenic mechanisms underlying synucleinopathies involve the spread and propagation of α-synuclein aggregates throughout the central nervous system and at least in part, through the ECS. We have used freely diffusing single-wall carbon Nanotubes (SWCNTs) to try to understand the effect of synucleinopathy on extracellular diffusion, as it is emerging as a critical component for propagation, communication and regulation in health and disease.

Method: Using SWCNTs single-particle tracking, we unravelled a significant increase in Substantia Nigra pars compacta extracellular diffusion values in the context of a-synuclein pathology accompanied by nigral neuron degeneration. Nonetheless, this model made it hard to disentangle the direct effect of neurodegeneration and synucleinopathy. We compared our previous model, which features neurodegeneration in the SN (our classic PD patient-derived Lewy bodies extract), versus those exhibiting abundant synuclein aggregopathy (pre-formed fibrils (PFF)). Single particle tracking has become a powerful tool for characterising some of the fundamental ECS properties at the nanoscale. The recording of long trajectories in the so-called “transparency window” of tissue permits the reconstruction of ECS maps with nanometric resolution, including instantaneous diffusion coefficients and estimation of channel width.

Results: Our results show that (i) SN and striatum present different diffusional regimes; (ii) the SN neurodegeneration model presents, as expected, increased diffusion regimes in the SN but none in the striatum, (iii) the presence of secondary aggregates in the striatum in the PFF model also causes an increased diffusion regime in the striatum. The sole spread of the synucleinopathy can, therefore, affect ECS diffusional parameters, thereby likely further contributing to its propagation. We hypothesise that these aggregates can affect the surrounding microenvironment, triggering inflammatory responses, which would widen the ECS.

Conclusion: Understanding the distinct effects of these synucleinopathy models on the ECS is crucial for unravelling the mechanisms underlying synuclein propagation, neurodegeneration, and associated clinical manifestations. Elucidating the interplay between aggregated α-synuclein and the ECS may unveil potential therapeutic targets to modulate synucleinopathy progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/understanding-diffusion-in-extracellular-space-in-synucleinopathy/