FUS aggregation following ischemic stroke favors brain astrocyte activation through inducing excessive autophagy

As is the case with neurodegenerative diseases, abnormal accumulation of aggregated proteins in neurons and glial are also known to implicate in the pathogenesis of ischemic stroke. However, the potential role of protein aggregates in brain ischemia remains largely unknown. Fused in Sarcoma (FUS) protein has a vital role in RNA metabolism and regulating cellular homeostasis. FUS pathology has been demonstrated in the formation of toxic aggregates and critically affecting cell viability in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but whether this also applies to neurological injury following cerebral ischemia is unclear. Herein, we demonstrated a critical role of aggregated FUS in astrocyte activation caused by cerebral ischemia and a possible underlying molecular mechanism. Cerebral ischemic injury significantly induced the formation of cytoplasmic FUS aggregates in reactive astrocytes and injured neurons, thereby aggravating neurofunctional damages and worsening stroke outcomes. Further analysis revealed that extranuclear aggregation of FUS in astrocytes was involved in the induction of excessive autophagy, which contributes to autophagic cell injury or death. In conclusion, our results reveal the important contribution of FUS aggregates in promoting astrocyte activation in stroke pathology independent of its transcriptional regulation activity. We thus propose that aggregation of FUS is an important pathological process in ischemic stroke and targeting FUS aggregates might be of unique therapeutic value in the development of future treatment strategies for ischemic stroke. FUS is essential for astrocytes to maintain cellular homeostasis through regulating the process of RNA metabolism including gene transcription, splicing, transport, and translation. In resting astrocytes, the small amount of FUS aggregates will be rapidly degraded though autophagy and proteasome pathways. However, the formation of large amounts of FUS aggregates exceeds the capacity of the cellular protein degradation systems because of the ubiquitin-proteasome pathway is impaired in cerebral ischemia. At this time, the compensatory activation of autophagy is induced to degrade FUS aggregates. Nevertheless, the continuously formed FUS aggregates could lead to excessive autophagy, thus resulting in astrocyte activation. [Display omitted] •Ischemic stroke significantly induces the formation of FUS aggregates.•The accumula