A New Phase of Networking: The Molecular Composition and Regulatory Dynamics of Mammalian Stress Granules

Millar, Seán; Huang, Jie; Schreiber, Karl J.; Tsai, Yi-Cheng; Won, Jiyun; Zhang, Jianping; Moses, Alan M.; Youn, Ji‐Young

doi:10.1021/acs.chemrev.2c00608

Cited by 30 publications

(33 citation statements)

References 259 publications

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Section: Neurodegenerative Diseasementioning

confidence: 99%

“…[98,[203][204][205] Among these diseases, AD is a widely investigated neurodegenerative disease that accounts for 70% of all dementia and affects the quality of human life. [203][204][205] Early diagnosis of AD is of vital importance because there is no certain treatment after the lesion has progressed in the late stage. [116,203] In 2020, Park et al demonstrated a dualantibody-modified GFET biosensor for multiplex detection of two AD biomarkers (Figure 11a).…”

Section: Neurodegenerative Diseasementioning

confidence: 99%

“…[ 121 ] Compared with commercial ELISA kits and single‐molecule array (Simoa) technology, the proposed GFET approach exhibited competitive LoD down to 231 fg mL −1 and a short sample‐to‐answer time of <15 min, indicating its great promise for POC diagnosis applications. [ 121,204 ]…”

Section: Prototypical Applicationsmentioning

confidence: 99%

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Graphene Transistors for In Vitro Detection of Health Biomarkers

Dai

Kong

Chen

et al. 2023

Adv Funct Materials

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Biomarkers are primary indicators for precise diagnosis and treatment. The early identification of health biomarkers has been sustained by the evolutionary success in sensor technologies. Among them, graphene field-effect transistor (GFET) biosensors have exhibited major advantages such as an ultrashort response time, high sensitivity, easy operation, capability of integration, and label-free detection. Owing to the atomic thickness, graphene restricts charge carrier flow merely at the material surface and responds to foreign stimuli directly, leading to effective signal acquisition and transmission. Here, this review summarizes the latest advances in GFET biosensors in a comprehensive manner that contains the device design, working principle, surface functionalization, and proof-of-concept applications. It provides a comprehensive survey of GFET biosensors with regard to biomarker analysis at the single-device level and integrated prototypes that include wearable sensors, biomimetic systems, healthcare electronics, and diagnostic platforms. Moreover, there is discussion on the long-standing research efforts and outlook for the future development of GFET sensor systems from lab to fab.

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Section: Neurodegenerative Diseasementioning

confidence: 99%

Section: Neurodegenerative Diseasementioning

confidence: 99%

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Graphene Transistors for In Vitro Detection of Health Biomarkers

Dai

Kong

Chen

et al. 2023

Adv Funct Materials

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“…The current studies reveal a likely interaction between native C9orf72 protein and PRMTs in regulating these pathways in C9orf72-mutation-mediated neurodegeneration. Recent studies have highlighted the importance of stress granule formation and requisite liquid-liquid phase separation as modulators of C9orf72 mutation-mediated cytotoxicity in cell-based models ( Liu et al, 2023 ; Millar et al, 2023 ). For example, C9orf72 has been demonstrated to be a regulator of the integrated stress response (ISR), facilitating stimulation of the unfolded protein response (UPR), inhibition of stress granule formation, and LLPS through interaction with eIF2a ( Zheng et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

Dane

Gill

Vieira

et al. 2023

Front. Cell. Neurosci.

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IntroductionIntronic repeat expansions in the C9orf72 gene are the most frequent known single genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeat expansions are believed to result in both loss-of-function and toxic gain-of-function. Gain-of-function results in the production of toxic arginine-rich dipeptide repeat proteins (DPRs), namely polyGR and polyPR. Small-molecule inhibition of Type I protein arginine methyltransferases (PRMTs) has been shown to protect against toxicity resulting from polyGR and polyPR challenge in NSC-34 cells and primary mouse-derived spinal neurons, but the effect in human motor neurons (MNs) has not yet been explored.MethodsTo study this, we generated a panel of C9orf72 homozygous and hemizygous knockout iPSCs to examine the contribution of C9orf72 loss-of-function toward disease pathogenesis. We differentiated these iPSCs into spinal motor neurons (sMNs).ResultsWe found that reduced levels of C9orf72 exacerbate polyGR15 toxicity in a dose-dependent manner. Type I PRMT inhibition was able to partially rescue polyGR15 toxicity in both wild-type and C9orf72-expanded sMNs.DiscussionThis study explores the interplay of loss-of-function and gain-of-function toxicity in C9orf72 ALS. It also implicates type I PRMT inhibitors as a possible modulator of polyGR toxicity.

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“…The stress granule (SG) proteome was obtained from RNAGranuleDB [55] by taking only Tier 1 SG proteins. The nucleolar proteome was derived from [56], by only accepting proteins with "Enhanced" or "Supported" nucleolar localization to gain a high-confidence dataset.…”

Section: Data Collection For Bioinformatics Analysismentioning

confidence: 99%

C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1

Nerom

Ahmed

Lázár

et al. 2023

Preprint

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Ras GTPase-activating protein-binding protein 1 (G3BP1) is the key protein driving the formation of cytoplasmic stress granules (SGs) by liquid-liquid phase separation (LLPS). It is a switch-like protein held in a closed and inactive state by intramolecular electrostatic interactions competitively opened by RNA, activating the protein and initiating its LLPS. Here we show that C9orf72-derived arginine-rich dipeptide repeats PR30 and GR30 (R-DPRs) present in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), also bind to G3BP1, switching it to an LLPS-competent open state much more effectively than RNA. Whereas RNA binds G3BP1 with micromolar affinity, and cannot initiate LLPS without crowding agents, R-DPRs exhibit a thousand-fold stronger binding to G3BP1, eliciting rapid LLPS even without crowding. The pathogenic effect of R-DPRs is also underscored by the slow transition of R-DPR-G3BP1 liquid droplets to aggregated, ThS-positive states that can recruit the ALS-linked protein hnRNPA2. Deletion constructs and molecular simulations show that R-DPR binding and LLPS are mediated via binding through the negatively charged intrinsically disordered region 1 (IDR1) of the protein, allosterically regulated by the positively charged IDR3. Bioinformatic analyses point to the strong mechanistic parallels of these effects with the interaction of R-DPRs with nuclear nucleophosmin (NPM1) and also suggest that R-DPRs also interact with many other similar nucleolar and stress-granule proteins, extending the underlying mechanism of R-DPR toxicity in cells.

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A New Phase of Networking: The Molecular Composition and Regulatory Dynamics of Mammalian Stress Granules

Cited by 30 publications

References 259 publications

Graphene Transistors for In Vitro Detection of Health Biomarkers

Graphene Transistors for In Vitro Detection of Health Biomarkers

Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a Type I protein arginine methyltransferase inhibitor reduces that toxicity

C9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1

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