Age‐related neurodegenerative diseases

Converging evidence indicates the dysregulation of unique cytosolic compartments called stress granules (SGs) might facilitate the accumulation of toxic protein aggregates that underlie many age‐related neurodegenerative pathologies (ANPs). SG dynamics are particularly susceptible to the cellular conditions that are commonly induced by aging, including the elevation in reactive oxygen species and increased concentration of aggregate‐prone proteins. In turn, the persistent formation of these compartments is hypothesized to serve as a seed for subsequent protein aggregation. Notably, the protein quality control (PQC) machinery responsible for inhibiting persistent SGs (e.g., Hsc70–BAG3) can become compromised with age, suggesting that the modulation of such PQC mechanisms could reliably inhibit pathological processes of ANPs. As exemplified in the context of accelerated aging syndromes (i.e., Hutchinson–Gilford progeria), PQC enhancement is emerging as a potential therapeutic strategy, indicating similar techniques might be applied to ANPs. Collectively, these recent findings advance our understanding of how the processes that might facilitate protein aggregation are particularly susceptible to aging conditions, and present investigators with an opportunity to develop novel targets for ANPs. Proposed mechanism by which age‐dependent stress granule (SG) dysregulation facilitates pathological aggregation of proteins. SGs are transient, cytosolic compartments that sequester messenger RNA upon cellular detection of stress factors, such as reactive oxygen species/reactive nitrogen species (ROS/RNS); upon the removal of a transient stressor, SG disassembly is facilitated by certain protein quality control mechanisms, specifically the Hsc70–BAG3 complex. Aging is associated with increased concentrations of ROS/RNS as well as aggregate‐prone polypeptides; such conditions are capable of inducing SG formation and inhibiting SG disassembly, respectively.