Abstract

In this seminar, I will discuss the relevance of intra- and extracellular proteostasis in countering disease-associated protein misfolding and aggregation, particularly in neurodegenerative diseases characterized by protein deposition. I will present recent findings that link the multifunctional Ca-binding S100 family proteins to neuroprotective functions as both intra- and extracellular chaperones. The focus will be on S100B , highlighting its structural properties and mechanisms underlying its holdase activity that mitigates the aggregation, phase separation, neurotoxicity, and cell-to-cell spreading of amyloidogenic proteins, notably tau and amyloid β. I will discuss the diverse activities and changes in the levels of S100 proteins across the neurodegeneration continuum and propose their protective role as an early response mechanism to intra- and extracellular proteostasis dysfunction.