Abstract:

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, despite the diversity in clinical symptoms, share a striking feature at the cellular level: the accumulation of insoluble aggregates of misfolded proteins that are sequestered in intraneuronal inclusion bodies. Besides mutations in disease-associated proteins that render them aggregation-prone, the decline of protein homeostasis (i.e. proteostasis) with aging is also believed to be a contributing factor to the accumulation of protein aggregates. As terminally misfolded proteins are intrinsically toxic, cells have developed mechanisms to minimize potential negative effects of protein aggregates on cell viability. Two main strategies that are at the cell’s disposal are either to eliminate terminally misfolded proteins by protein degradation or to spatially separate them from critical processes by allocating them to destinated intracellular locations through protein sequestration. While it is well established that conditions that cause proteotoxic stress activate mechanisms that regulate degradation and sequestration of misfolded proteins, it is less clear to what extent these two processes are intertwined. Protein sequestration seems to be less of a direct solution to the problem at hand than protein degradation as sequestration merely postpones the point at which the misfolded proteins must be dealt with or, alternatively, the point at which they will cause toxicity. Chemical inhibition of protein degradation results in the formation of inclusion bodies, suggesting that sequestration is a second line of defense that only comes in play under conditions where intracellular protein degradation fails to timely eliminate misfolded proteins. However, could it be that protein sequestration is not just a backup mechanism but also a first responder during proteotoxic stress? Our recent study suggests this to be the case and supports a model where protein sequestration occurs before the degradation machinery is overloaded, thereby preserving a level of protein degradation that is required to rapidly restore proteostasis (Xu et al., 2023). Interestingly, transient sequestration of misfolded proteins at stress granules turned out to be of particular importance, suggesting an additional role for these subcellular, stress-induced structures, next to their well-established connection to the regulation of protein synthesis (Sohnel and Brandt, 2023).