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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. [ABSTRACT FROM AUTHOR]

Posttranscriptional RNA modification has become a revolutionary clinical tool to improve the underlying condition in genetic disorders. The cell achieves translational regulation through sequence and/or structural elements that recruit specific positive- or negative-acting factors to mRNAs. Targeting mRNA expression offers a less invasive therapeutic approach than other well-known gene therapy approaches. We have utilized our understanding of mRNA translational regulation to develop a novel disease-modifying treatment called the "Tethered mRNA Amplifier." Specifically, our approach forces a key positive-acting mRNA regulator, polyadenosine binding protein (PABPC1), to bind and remain resident on the target mRNA. This enhances the target mRNA's expression precisely and restores deficient protein levels to normal. This approach effectively increases the steady-state expression level of several transcripts associated with haploinsufficiency disorders in cell culture., (© 2024. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)