The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood, although it is best known for its critical role in stress granule formation. Aberrant stress granule dynamics are increasingly recognized as a hallmark of several neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), frontotemporal dementia (FTD), and Parkinson’s disease (PD).
In this new study, Sarayu Ramakrishna, Laura Ryan and Sung Min Son in the Rubinsztein lab 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, researchers observed 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. By linking G3BP1 to organelle function and proteostasis, this study underscores a physiological function of G3BP1 with implications for multiple neurodegenerative diseases characterized by protein aggregation and trafficking defects. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.