The potential role of liquid-liquid phase separation in the cellular fate of the compartments for unconventional protein secretion.

Eukaryotic cells have developed intricate mechanisms for biomolecule transport, particularly in stressful conditions. This interdisciplinary study delves into unconventional protein secretion (UPS) pathways activated during starvation, facilitating the export of proteins bypassing most of the components of the classical secretory machinery. Specifically, we focus on the underexplored mechanisms of the GRASP's role in UPS, particularly in biogenesis and cargo recruitment for the vesicular-like compartment for UPS. Our results show that liquid-liquid phase separation (LLPS) plays a key role in the coacervation of Grh1, the GRASP yeast homologue, under starvation-like conditions. This association seems a precursor to the Compartment for Unconventional Protein Secretion (CUPS) biogenesis. Grh1's self-association is regulated by electrostatic, hydrophobic, and hydrogen-bonding interactions. Importantly, our study demonstrates that phase-separated states of Grh1 can recruit UPS cargo under starvation-like situations. Additionally, we explore how the coacervate liquid-to-solid transition could impact cells' ability to return to normal post-stress states. Our findings offer insights into intracellular protein dynamics and cell adaptive responses to stress.

More than a Rumor Spreads in Parkinson's Disease.

As Parkinson's disease progresses, a massive loss of dopaminergic neurons is accompanied by accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies and Lewy neurites. Inclusions first appear in olfactory bulb and enteric neurons then in ascendant neuroanatomical interconnected areas, and finally, in late stages of the disease, Lewy bodies are observed in a substantia nigra pars compacta with clear signs of neuronal loss. It is believed that the spreading of Lewy bodies through the nervous system is a consequence of the cell-to-cell propagation of αSyn, that can occur via sequential steps of secretion and uptake. Certain pathological forms of transmitted αSyn are able to seed endogenous counterparts in healthy recipient cells, thus promoting the self-sustained cycle of inclusion formation, amplification and spreading, that ultimately underlies disease progression. Here we review the cell-to-cell propagation of αSyn focusing on its role in the progression of Parkinson's disease.