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Last update 08 May 2025

PPP1R15A

Last update 08 May 2025

Basic Info

Synonyms

GADD34, Growth arrest and DNA damage-inducible protein GADD34, growth arrest and DNA-damage-inducible 34

+ [5]

Introduction

Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress (PubMed:26095357, PubMed:26742780). Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1 (PubMed:14718519). May promote apoptosis by inducing p53/TP53 phosphorylation on 'Ser-15' (PubMed:14635196). Plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux (PubMed:32978159). Acts also a viral restriction factor by attenuating HIV-1 replication (PubMed:31778897). Mechanistically, mediates the inhibition of HIV-1 TAR RNA-mediated translation (PubMed:31778897). (Microbial infection) Promotes enterovirus 71 replication by mediating the internal ribosome entry site (IRES) activity of viral 5'-UTR.

Drugs associated with PPP1R15A

Icerguastat

Target

PPP1R15A

Mechanism

PPP1R15A inhibitors

Active Org.

Inflectis Bioscience SAS [+1]

Originator Org.

The Medical Research Council

Active Indication

Amyotrophic Lateral Sclerosis [+1]

Inactive Indication

Multiple Sclerosis

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

IFB-048

Target

PPP1R15A

Mechanism

PPP1R15A inhibitors

Active Org.

Inflectis Bioscience SAS

Originator Org.

Inflectis Bioscience SAS

Active Indication

Multiple Sclerosis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GL-GP inhibitors(Boehringer Ingelheim)

Target

PPP1R15A x PYG

Mechanism

PPP1R15A inhibitors [+1]

Active Org.-

Originator Org.

Boehringer Ingelheim Pharma GmbH & Co., KG

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with PPP1R15A

NCT05508074

/ CompletedPhase 2

A Double-blind, Placebo-controlled, Exploratory Randomised Clinical Trial to Assess the Safety and Efficacy of IFB-088 Plus Riluzole 100 mg vs Placebo Plus Riluzole 100 mg in Patients With Bulbar-onset Amyotrophic Lateral Sclerosis.

Prospective, international, randomised, double-blind, placebo controlled, multicentre, parallel group study. Patients will be randomised in a 2:1 allocation ratio to receive either IFB-088 + riluzole 100 mg or placebo + riluzole 100 mg. This clinical trial is an exploratory study, designed to show a signal of efficacy of IFB-088 through ALSFRS-R, MITOS and King's College. Respiratory function will be followed through SVC. Biomarkers and quality of life will also be evaluated throughout the study.
Patients will be treated over a 6-month period. After a screening/consent visit, patients will undergo clinic visits at randomisation (V0), at 2 weeks (V1), and at months 1 (V2), 3 (V3) and 6 (V4). One week after V0, the patient will undergo urine analysis (dipstick)and blood sampling for measurement of creatinine
, as well as blood sampling for measurement of creatinine and calculation of eGFR at months 2, 4 and 5. At the V2 visit, in addition to other assessments, patients will undergo blood sampling for PK measurements and urine sampling for crystalluria examination. Blood and urine chemistry, as well as physical examination and vital signs assessment to assess safety will be performed at each visit for safety purpose and crystalluria examination will be repeated at the follow-up visit, performed one month ± one week after V4.

Start Date02 Dec 2022

Sponsor / Collaborator

Inflectis Bioscience SAS

NCT03610334

/ CompletedPhase 1

A Double-blind, Randomized, Placebo-controlled, Combined Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of IFB-088, in Healthy Volunteers

This is the first study of single and multiple doses of IFB-088 in human subjects. The current study is designed to assess in the first part, the safety, tolerability, plasma and urine pharmacokinetics (PK) of single oral doses of IFB-088 in healthy subjects (Single Ascending Doses - SAD) and in a second part safety, tolerability, plasma and urine pharmacokinetics (PK) of multiple oral doses of IFB-088 in healthy subjects (Multiple Ascending Doses - MAD)

Start Date21 Jun 2018

Sponsor / Collaborator

Inflectis Bioscience SAS

[+4]

100 Clinical Results associated with PPP1R15A

100 Translational Medicine associated with PPP1R15A

0 Patents (Medical) associated with PPP1R15A

588

Literatures (Medical) associated with PPP1R15A

01 May 2025·Journal of Cell Science

Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules

Article

Author: Smyrnias, Ioannis ; Sun, Zhaozhi ; Taylor, J. Paul ; Locker, Nicolas ; Safakli, Rahme ; Freibaum, Brian D. ; Relton, Emily ; Ruggieri, Alessia ; Lopez-Nieto, Marta

ABSTRACTTo rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that the SG formation and UPRmt pathways are intertwined and communicate. UPRmt induction results in eIF2α phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 (also known as PPP1R15A) during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that might contribute to restoring mitochondrial functions under stressful conditions.

02 Apr 2025·ACS Chemical Neuroscience

Interplay of Endoplasmic Reticulum Stress, Inflammation, Apoptosis, and Oxidative Stress in Corticosteroid-Induced Anxiety and Depression: Exploring Therapeutic Potential of Hydrogen Sulfide and Sertraline

Article

Author: Azzam, May A. ; ElMonier, Asmaa A. ; Abd-Elmawla, Mai A. ; Gad, Enas S.

Prolonged exposure to corticosteroids (CORTs) triggers depression and anxiety symptoms either endogenously or exogenously via stimulating endoplasmic reticulum stress (ERS). The study assessed the therapeutic implications of hydrogen sulfide (H₂S) versus sertraline (SERT) in alleviating anxiety and depression induced by CORTs through the modulation of ERS and its inflammatory, oxidative, and apoptotic consequences. Rats were subdivided into four groups: control, CORT (20 mg/kg), NaHS (100 μmol/kg), and SERT (10 mg/kg) for 21 days. Behavioral and histological examinations of the cerebral cortex were performed. The levels of CHOP, GADD34, EIF2AK3, GRP78, caspase 3, and miR-146a were analyzed using qRT-PCR. The levels of CORTs, serotonin, BDNF, TNF-α, BCL2, NRF2, and ATF4 were measured using ELISA, whereas those of IL-1β and BAX were measured using immunohistochemical techniques. Total and phosphorylated PERK were assessed via western blotting, whereas GSH and MDA were assessed via a colorimetric assay. In the present study, CORTs upregulated the gene expression of CHOP, GADD34, EIF2AK3, GRP78, and Caspase 3, whereas it downregulated that of miR-146a. The levels of serotonin, BDNF, BCL2, GSH, and NRF2 were decreased, whereas those of ATF4, TNF-α, IL-1β, BAX, and MDA were elevated. On the contrary, NaHS and SERT reversed all the above-mentioned changes. H₂S shows promise in counteracting anxiety and depression symptoms induced by CORTs by targeting ERS cascades, mitigating inflammation, oxidative insults, and apoptosis in the cerebral cortex. H₂S elicits neuroprotective effects by targeting the miR-146a-3p/GRP78/CHOP/PERK/ATF4/GADD34 signaling pathway and regulating apoptotic markers BAX/BCL2 and inflammatory markers TNF-α and/IL-1β. Compared with SERT, H₂S exhibited superior anxiolytic and antidepressive effects.

28 Feb 2025·The FASEB Journal

Dolutegravir induces endoplasmic reticulum stress at the blood–brain barrier

Article

Author: Qu, Qing Rui ; Bendayan, Reina ; Hoque, Md. Tozammel ; Huang, Chang

AbstractDolutegravir (DTG)‐based antiretroviral therapy is the contemporary first‐line therapy to treat HIV infection. Despite its efficacy, mounting evidence has suggested a higher risk of neuropsychiatric adverse effect (NPAE) associated with DTG use, with a limited understanding of the underlying mechanisms. Our laboratory has previously reported a toxic effect of DTG but not bictegravir (BTG) in disrupting the blood–brain barrier (BBB) integrity. The current study aimed to investigate the underlying mechanism of DTG toxicity. Primary cultures of mouse brain microvascular endothelial cells were treated with DTG and BTG at therapeutically relevant concentrations. RNA sequencing, qPCR, western blot analysis, and cell stress assays (Ca2+ flux, H2DCFDA, TMRE, MTT) were applied to assess the results. The gene ontology (GO) analysis revealed an enriched transcriptome signature of endoplasmic reticulum (ER) stress following DTG treatment. We demonstrated that therapeutic concentrations of DTG but not BTG activated the ER stress sensor proteins (PERK, IRE1, p‐IRE1) and downstream ER stress markers (eIF2α, p‐eIF2α, Hspa5, Atf4, Ddit3, Ppp1r15a, Xbp1, spliced‐Xbp1). In addition, DTG treatment resulted in a transient Ca2+ flux, an aberrant mitochondrial membrane potential, and a significant increase in reactive oxygen species in treated cells. Furthermore, we found that prior treatment with ER sensor or ER stress inhibitors significantly mitigated the DTG‐induced downregulation of tight junction proteins (Zo‐1, Ocln, Cldn5) and elevation of pro‐inflammatory cytokines and chemokines (Il6, Il23a, Il12b, Cxcl1, Cxcl2). The current study provides valuable insights into DTG‐mediated cellular toxicity mechanisms, which may serve as a potential explanation for DTG‐associated NPAEs in the clinic.

News (Medical) associated with PPP1R15A

29 Oct 2024

·www.prnewswire.com

Discovery of cancer risk associations for six novel genes

REYKJAVIK, Iceland, Oct. 29, 2024 /PRNewswire/ --Scientists at deCODE genetics/Amgen, and their collaborators have discovered six novel genes with rare germline variants that associate with cancer risk. The findings are published today in Nature Genetics under the title "Gene-based burden tests of rare germline variants identify six cancer susceptibility genes". Continue Reading Kari Stefansson senior author of the paper, “Gene-based burden tests of rare germline variants identify six cancer susceptibility genes”, published today in Nature Genetics, discusses the paper with Erna V. Ivarsdottir first author on the paper. Kari Stefansson CEO of deCODE genetics and senior author on the paper in Nature Genetics, with Erna V. Ivarsdottir scientists at deCODE genetics and first author. A subset of cancers arises in individuals who are born with rare sequence variants that significantly alter their cancer risk. The discovery of such variants, like those in the BRCA1- and BRCA2 genes, has led to improved early cancer detection and the development of targeted therapies, ultimately reducing the cancer burden and improving prognosis of those carrying these mutations. In this study, the scientists analysed three large genetic datasets from individuals of European descent, including 130,991 cancer patients and 733,486 controls. Through a gene-based burden association analysis across 22 different cancer types, they found four novel genes associated with a risk of developing cancer; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer, and CMTR2 for both lung cancer and cutaneous melanoma. The relative increase in cancer risk conferred by these variants was substantial (90-295%), but it should be noted that the design of the study does not allow accurate assessment of absolute lifetime cancer risk. Additionally, the researchers found the first genes with rare variants that are associated with a decreased risk of cancer. Specifically, loss of AURKB was found to protect against any cancer type, and loss of PPP1R15A was associated with 53% lower risk of breast cancer. This suggests that inhibition of PPP1R15A may be a therapeutic option for breast cancer. The study revealed new insight into the biological mechanisms involved in cancer predisposition that will hopefully lead to better screening and treatment strategies. Video - Photo - SOURCE deCODE genetics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

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PPP1R15A

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