Aberrant stress granule dynamics and aggrephagy in als pathogenesis

Abstract

Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that un-dergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cy-totoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defec-tive aggrephagy has been causally linked to various neurodegenerative diseases, including amyo-trophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of au-tophagy and ALS pathogenesis.