α-Synuclein emulsifies TDP-43 prion-like domain – RNA liquid droplets to promote heterotypic amyloid fibrils

Abstract

Many neurodegenerative diseases including frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA), etc., show colocalized deposits of TDP-43 and α-synuclein (αS) aggregates. To understand whether these colocalizations are driven by specific molecular interactions between the two proteins, we previously showed that the prion-like C-terminal domain of TDP-43 (TDP-43PrLD) and αS synergistically interact to form neurotoxic heterotypic amyloids in homogeneous buffer conditions. However, it remains unclear whether and how αS modulates TDP-43 present within liquid droplets and biomolecular condensates called stress granules (SGs). Here, using cell culture and in vitro TDP-43PrLD - RNA liquid droplets as models along with microscopy, nanoscale spatially-resolved spectroscopy, and other biophysical analyses, we uncover the interactions of αS with phase-separated droplets. We learn that αS acts as a Pickering agent by forming clusters on the surface of TDP-43PrLD - RNA droplets and emulsifying them. The hardening of the droplets that follow by αS aggregates on the periphery, nucleates the formation of heterotypic TDP-43PrLD amyloid fibrils with structures distinct from those derived from homogenous solutions. Together, these results reveal an intriguing property of αS as a Pickering agent in interacting with SGs and unmask the hitherto unknown role of αS in modulating TDP-43 proteinopathies.

Heterotypic Seeding Generates Mixed Amyloid Polymorphs

“…Amyloid plaques have been shown to contain proteins such as tau and alpha synuclein in addition to Aβ 20,21,27 ; yet how the coaggregation/cross-seeding with these proteins can alter the aggregation pathway of Aβ remains to be fully understood. The interest in understanding heterotypic amyloid interactions have grown significantly in recent years, leading to key insights into how they may affect the aggregation process 19,22,[28][29][30][31][32] . The interactions of Aβ with tau have been investigated, and it is known that tau inhibits maturation of Aβ oligomers to the fibrillar stage 33 .…”