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Stress granules sequester Alzheimer's disease-associated gene transcripts and regulate disease-related neuronal proteostasis.

ABSTRACT: Environmental and physiological stresses can accelerate Alzheimer's disease (AD) pathogenesis. Under stress, a cytoplasmic membraneless structure termed a stress granule (SG) is formed and is associated with various neurodegenerative disorders, including AD. SGs contain translationally arrested mRNAs, suggesting that impaired RNA metabolism in neurons causes AD progression; however, the underlying mechanism remains unclear. Here, we identified numerous mRNAs and long non-coding RNAs that are directly targeted by the SG core proteins G3BP1 and G3BP2. They redundantly target RNAs before and after stress conditions. We further identified RNAs within SGs, wherein AD-associated gene transcripts accumulated, suggesting that SGs can directly regulate AD development. Furthermore, gene-network analysis revealed a possible link between the sequestration of RNAs by SGs and the impairment of protein neurohomeostasis in AD brains. Together, our study provides a comprehensive RNA regulatory mechanism involving SGs, which could be targeted therapeutically to slow AD progression mediated by SGs.

SUBMITTER: Sato K

PROVIDER: S-EPMC10258020 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Stress granules sequester Alzheimer's disease-associated gene transcripts and regulate disease-related neuronal proteostasis.

Sato Kaoru K Takayama Ken-Ichi KI Inoue Satoshi S

Aging 20230522 10

Environmental and physiological stresses can accelerate Alzheimer's disease (AD) pathogenesis. Under stress, a cytoplasmic membraneless structure termed a stress granule (SG) is formed and is associated with various neurodegenerative disorders, including AD. SGs contain translationally arrested mRNAs, suggesting that impaired RNA metabolism in neurons causes AD progression; however, the underlying mechanism remains unclear. Here, we identified numerous mRNAs and long non-coding RNAs that are dir ...[more]

PMID: 37219408

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Project description:Failed proteostasis is a well-documented feature of Alzheimer's disease, particularly, reduced protein degradation and clearance. However, the contribution of failed proteostasis to neuronal circuit dysfunction is an emerging concept in neurodegenerative research and will prove critical in understanding cognitive decline. Our objective is to convey Alzheimer's disease progression with the growing evidence for a bidirectional relationship of sleep disruption and proteostasis failure. Proteostasis dysfunction and tauopathy in Alzheimer's disease disrupts neurons that regulate the sleep-wake cycle, which presents behavior as impaired slow wave and rapid eye movement sleep patterns. Subsequent sleep loss further impairs protein clearance. Sleep loss is a defined feature seen early in many neurodegenerative disorders and contributes to memory impairments in Alzheimer's disease. Canonical pathological hallmarks, β-amyloid, and tau, directly disrupt sleep, and neurodegeneration of locus coeruleus, hippocampal and hypothalamic neurons from tau proteinopathy causes disruption of the neuronal circuitry of sleep. Acting in a positive-feedback-loop, sleep loss and circadian rhythm disruption then increase spread of β-amyloid and tau, through impairments of proteasome, autophagy, unfolded protein response and glymphatic clearance. This phenomenon extends beyond β-amyloid and tau, with interactions of sleep impairment with the homeostasis of TDP-43, α-synuclein, FUS, and huntingtin proteins, implicating sleep loss as an important consideration in an array of neurodegenerative diseases and in cases of mixed neuropathology. Critically, the dynamics of this interaction in the neurodegenerative environment are not fully elucidated and are deserving of further discussion and research. Finally, we propose sleep-enhancing therapeutics as potential interventions for promoting healthy proteostasis, including β-amyloid and tau clearance, mechanistically linking these processes. With further clinical and preclinical research, we propose this dynamic interaction as a diagnostic and therapeutic framework, informing precise single- and combinatorial-treatments for Alzheimer's disease and other brain disorders.

Dataset Information

Stress granules sequester Alzheimer's disease-associated gene transcripts and regulate disease-related neuronal proteostasis.

Publications

Stress granules sequester Alzheimer's disease-associated gene transcripts and regulate disease-related neuronal proteostasis.

Similar Datasets

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