An emerging role for stress granules in neurodegenerative disease and hearing loss

Martin, Jack; Dawson, Sally J.; Gale, Jonathan E.

doi:10.1016/j.heares.2022.108634

Cited by 7 publications

(4 citation statements)

References 135 publications

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“…To further investigate whether HFD regulates the local stress responses, a marker of stress granules (Ras GTPase-activating protein-binding protein 1, also known as GAP SH3 domain-binding protein 1) was quantified using an anti-G3BP1 antibody. Stress granules (SGs) are membrane-free cytosolic aggregations of RNA-binding proteins that form in response to stress and are essential for maintenance of cochlear function [ 23 , 24 ]. Recent studies suggest that age-related stress granule dysfunction may be one of the main mechanisms underlying age-related hearing loss and neurodegenerative diseases [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Sex differences in hearing impairment due to diet-induced obesity in CBA/Ca mice

et al. 2023

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Background Obesity is an independent risk factor for hearing loss. Although attention has focused on major obesity comorbidities such as cardiovascular disease, stroke, and type 2 diabetes, the impact of obesity on sensorineural organs, including the auditory system, is unclear. Using a high-fat diet (HFD)-induced obese mouse model, we investigated the impact of diet-induced obesity on sexual dimorphism in metabolic alterations and hearing sensitivity. Methods Male and female CBA/Ca mice were randomly assigned to three diet groups and fed, from weaning (at 28 days) to 14 weeks of age, a sucrose-matched control diet (10 kcal% fat content diet), or one of two HFDs (45 or 60 kcal% fat content diets). Auditory sensitivity was evaluated based on the auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and ABR wave 1 amplitude at 14 weeks of age, followed by biochemical analyses. Results We found significant sexual dimorphism in HFD-induced metabolic alterations and obesity-related hearing loss. Male mice exhibited greater weight gain, hyperglycemia, increased ABR thresholds at low frequencies, elevated DPOAE, and lower ABR wave 1 amplitude compared to female mice. The hair cell (HC) ribbon synapse (CtBP2) puncta showed significant sex differences. The serum concentration of adiponectin, an otoprotective adipokine, was significantly higher in female than in male mice; cochlear adiponectin levels were elevated by HFD in female but not male mice. Adiponectin receptor 1 (AdipoR1) was widely expressed in the inner ear, and cochlear AdipoR1 protein levels were increased by HFD, in female but not male mice. Stress granules (G3BP1) were significantly induced by the HFD in both sexes; conversely, inflammatory (IL-1β) responses were observed only in the male liver and cochlea, consistent with phenotype HFD-induced obesity. Conclusions Female mice are more resistant to the negative effects of an HFD on body weight, metabolism, and hearing. Females showed increased peripheral and intra-cochlear adiponectin and AdipoR1 levels, and HC ribbon synapses. These changes may mediate resistance to HFD-induced hearing loss seen in female mice.

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Section: Resultsmentioning

confidence: 99%

Sex differences in hearing impairment due to diet-induced obesity in CBA/Ca mice

et al. 2023

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“…Of note, SGs sequester key proteins that form pathological protein aggregates often associated with neurodegenerative diseases in addition to AD, such as TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS). 14,15,89,90 The idea that different SG subtypes may form in a cell type-and stressor-specific manner suggests that they may contribute differentially to the pathogenesis of each neurodegenerative disease in each context. Remarkably, therapeutic approaches based on modulation of SG-mediated RNA metabolism have been strikingly successful in delaying TDP-43-mediated ALS progression, 91 suggesting a new era in which therapeutics that target SG-mediated RNA metabolism may also modify disease progression in other neurodegenerative diseases, including AD.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, in addition to various other/external stressors, Aβ and tau can also be stressors, suggesting that they induce a feedback regulation that accelerates SG formation to exacerbate AD symptoms. Of note, SGs sequester key proteins that form pathological protein aggregates often associated with neurodegenerative diseases in addition to AD, such as TAR DNA‐binding protein 43 (TDP‐43) in amyotrophic lateral sclerosis (ALS) 14,15,89,90 . The idea that different SG subtypes may form in a cell type‐ and stressor‐specific manner suggests that they may contribute differentially to the pathogenesis of each neurodegenerative disease in each context.…”

Section: Discussionmentioning

confidence: 99%

Stress granule‐mediated RNA regulatory mechanism in Alzheimer's disease

Sato,

Takayama,

Inoue

2023

Geriatrics Gerontology Int

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Living organisms experience a range of stresses. To cope effectively with these stresses, eukaryotic cells have evolved a sophisticated mechanism involving the formation of stress granules (SGs), which play a crucial role in protecting various types of RNA species under stress, such as mRNAs and long non‐coding RNAs (lncRNAs). SGs are non‐membranous cytoplasmic ribonucleoprotein (RNP) granules, and the RNAs they contain are translationally stalled. Importantly, SGs have been thought to contribute to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). SGs also contain multiple RNA‐binding proteins (RBPs), several of which have been implicated in AD progression. SGs are transient structures that dissipate after stress relief. However, the chronic stresses associated with aging lead to the persistent formation of SGs and subsequently to solid‐like pathological SGs, which could impair cellular RNA metabolism and also act as a nidus for the aberrant aggregation of AD‐associated proteins. In this paper, we provide a comprehensive summary of the physical basis of SG‐enriched RNAs and SG‐resident RBPs. We then review the characteristics of AD‐associated gene transcripts and their similarity to the SG‐enriched RNAs. Furthermore, we summarize and discuss the functional implications of SGs in neuronal RNA metabolism and the aberrant aggregation of AD‐associated proteins mediated by SG‐resident RBPs in the context of AD pathogenesis. Geriatr Gerontol Int 2023; ••: ••–••.

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“…Any discussion of the role of the HSPB8-BAG3-HSP70 complex in facilitating autophagy in the heart or the brain is not complete without an introduction to a new area of great interest and potential therapeutic use: stress granules [ 37 ]—stress granules (SGs) are membrane-less cytosolic assemblies that form in response to stress and have been associated with diseases as diverse as hearing loss, neurodegenerative disease, and heart failure [ 38 ]. That BAG3 might play a role with the development and the maintenance of functional stress granules was supported by the finding that the HSPB8-BAG3_HSP70 chaperone complex maintains the integrity of the stress granule and prevents the accumulation of dysfunctional complexes in stress granules during stress [ 39 ].…”

Section: Cellular Function Of Bag3mentioning

confidence: 99%

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

Brenner

Choudhary

McCormick

et al. 2023

Cells

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BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolded proteins and damaged organelles, inhibits apoptosis, maintains the homeostasis of the mitochondria, and facilitates excitation contraction coupling through the L-type calcium channel and the beta-adrenergic receptor. High levels of BAG3 are associated with insensitivity to chemotherapy in malignant cells whereas both loss of function and gain of function variants are associated with cardiomyopathy.

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An emerging role for stress granules in neurodegenerative disease and hearing loss

Cited by 7 publications

References 135 publications

Sex differences in hearing impairment due to diet-induced obesity in CBA/Ca mice

Sex differences in hearing impairment due to diet-induced obesity in CBA/Ca mice

Stress granule‐mediated RNA regulatory mechanism in Alzheimer's disease

BAG3: Nature’s Quintessential Multi-Functional Protein Functions as a Ubiquitous Intra-Cellular Glue

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