Under stress, cells form cytoplasmic, membraneless organelles via liquid–liquid phase separation, known as stress granules. Dysregulated assembly and disassembly of stress granules is closely linked to pathological protein aggregation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We discovered that metabolic stress induces a distinct subclass of stress granules, which we have termed energy-stress granules. In both patient-derived induced pluripotent stem cell (iPSC) neurons and cerebral organoids from ALS/FTD cases, intrinsic metabolic deficiencies increased the frequency of energy-stress granule formation, thereby elucidating how metabolic dysregulation contributes to proteostasis imbalance during disease pathogenesis. This study was published in Nature Communications in 2022.
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