Year: 2022
Type: article
Abstract: Energy metabolism and membraneless organelles have been implicated in human diseases including neurodegeneration. How energy deficiency regulates ribonucleoprotein particles such as stress granules (SGs) is still unclear. Here we identified a unique type of granules induced by energy deficiency under physiological conditions and uncovered the mechanisms by which the dynamics of diverse stress-induced granules are regulated. Severe energy deficiency induced the rapid formation of energy deficiency-induced stress granules (eSGs) independently of eIF2α phosphorylation, whereas moderate energy deficiency delayed the clearance of conventional SGs. The formation of eSGs or the clearance of SGs was regulated by the mTOR-4EBP1-eIF4E pathway or eIF4A1, involving assembly of the eIF4F complex or RNA condensation, respectively. In neurons or brain organoids derived from patients carrying the C9orf72 repeat expansion associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the eSG formation was enhanced, and the clearance of conventional SGs was impaired. These results reveal a critical role for intracellular energy in the regulation of diverse granules and suggest that disruptions in energy-controlled granule dynamics may contribute to the pathogenesis of relevant diseases.
Source: Nature Communications
Institution: Johns Hopkins University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Muscular Dystrophy Association, Johns Hopkins University, Maryland Stem Cell Research Fund, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: G1092843790, G2194601260, G2268721601, G2433881538, G2602914923, Fourier Transform Orbitrap Fusion Lumos Tribrid Mass Spectrometer with ETD, G3201025306, G3497853625, G6003395801, G7150101005, G722579841, Molecular Basis of Pathogenic Cascades in ALS/FTD Initiated from C9orf72 Hexanucleotide Repeat Expansion, Mechanisms of Novel Regulators of Proteotoxicity and Quality Control Associated with ALS/FTD, Investigating the Novel Disease Pathways Associated with C9orf72-Linked ALS/FTD, Investigating Dysregulation of Stress-related Ribonucleoprotein Granules and Functions of Associated RNA-binding Proteins in ALS/FTD
OpenAlex ID: W4296896693