The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.
Sarayu Ramakrishna, Laura Ryan, S. Son et al.· Cell Death and Differentiati...· 0 citations
High-throughput single-cell omics of non-human primate brain tissue provides a powerful platform to investigate the molecular basis of brain aging. Here, we present a comprehensive transcriptomic and chromatin accessibility atlas of 2,955,873 nuclei from eight brain regions of 23 female cynomolgus macaques spanning the adult lifespan, including exceptionally old individuals. Our analyses reveal dynamic, cell-subtype- and region-specific age-related changes in core brain functions, including synaptic communication and axon myelination. We identify multicellular networks in the pons and medulla as a previously unrecognized hotspot of primate brain aging, highlighting white matter vulnerability as a central feature of aging. Integration with human brain aging and neurodegeneration datasets reveals both shared and divergent molecular mechanisms. We further define transcription factors and age-related chromatin remodeling programs linked to longevity and neurodegeneration. This spatiotemporal atlas establishes a foundational framework for understanding the cellular and regulatory architecture of primate brain aging and its links to disease.