Soledad Celej

Nahuel Foressi, Leandro Cruz Rodríguez and M. Soledad Celej

Dto. de Química Biológica, CIQUIBIC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina

Liquid-liquid phase separation (LLPS) is currently recognized as a common mechanism involved in the regulation of a number of spatiotemporal cellular functions. On the other hand, LLPS has been related to the biogenesis of several neurodegenerative disorders since many proteins that undergo aberrant phase separation are also found in pathological aggregates. Therefore, the formation of mixed protein coacervates may constitute a risk factor in overlapping neuropathologies, such as Parkinson’s (PD) and Alzheimer’s (AD) diseases.

Within this context, we first evaluated the homotypic and heterotypic phase behaviour of α-synuclein (AS) and Tau, linked to PD and AD, respectively. Then, we explored the influence of biologically relevant molecules, such as the hydrotrope ATP and the biogenic polyamines Spermine (Sp) and Spermidine (Spm) on AS and Tau LLPS.

AS showed a low propensity to form homotypic liquid droplets, yet phase separated into liquid condensates that maturated over time in the presence of Sp and Tau. ATP and Spm instead, induced a rapid formation of mesh-like non-amyloid aggregates. On the other hand, whereas Tau easily formed electrostatic droplets that dissolved at high ionic strength, heterotypic condensates were more resistant to electrostatic screening. ATP increased the fluidity of synergic coacervates and completely abolished droplet formation at high salt concentration. On the contrary, polyamines induced deformation and rigidity of homotypic and heterotypic Tau condensates, with the appearance of droplets containing ThioS aggregates in the presence of Sp.

Overall, these results provide support for a mechanism in which mixed condensates might contribute to the biogenesis of AS/Tau pathologies and highlight the diverse effect of biomolecules on LLPS of these amyloidogenic proteins.

Acknowledgements: Agencia-FONCyT, CONICET and SECyT-UNC for financial support.