DeCure for Proteasome-associated autoinflammatory syndrome 4
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for proteasome-associated autoinflammatory syndrome 4 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleProteasome-associated autoinflammatory syndrome 4 maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for proteasome-associated autoinflammatory syndrome 4 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
proteasome assembly chaperone 2 (PSMG2) — PSMG2 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8QYL · 2.67 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Proteasome-associated autoinflammatory syndrome 4 is one of the proteasome-associated autoinflammatory syndromes (PRAAS) caused by loss-of-function mutations in genes encoding proteasome subunits or assembly factors. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins, which is accompanied by a type I interferon signature. The underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I interferon under sterile conditions is the unfolded protein response (UPR), which is typically initiated in response to an accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. The observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause-and-effect relationship between proteasome impairment and interferonopathy onset.
The review from 2019 discusses pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling cascade is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets. The review from 2022 notes that most if not all syndromes caused by proteostasis perturbations exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses.
The 2020 review on autoinflammatory dermatoses states that although IL‑1 beta and the inflammasomes as its critical regulators are very important in autoinflammation, not all patients respond to inhibition of this signalling pathway. Several autoinflammatory diseases were associated with mutations in proteasome-immunoproteasome components. The coming years will show whether inflammatory dermatoses will be increasingly treated with suppression of the innate immune system in addition to inhibition of adaptive immunity. No clinical trial data, survival figures, or response rates for any drug are reported in these abstracts. What is still missing is any completed clinical trial testing a specific intervention in patients with proteasome-associated autoinflammatory syndrome 4, as well as patient stratification strategies and dedicated funding for such trials.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Frontiers in Immunology · 2019 · 80 citations · open access
Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)
AbstractType I interferonopathies cover a phenotypically heterogeneous group of rare genetic diseases including the recently described proteasome-associated autoinflammatory syndromes (PRAAS). By definition, PRAAS are caused by inherited and/or de novo loss‒of‒function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature. The observation that, similarly to pathogens, proteasome dysfunctions are potent type I IFN inducers is quite unexpected and, up to now, the underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress). The recent observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause‒and‒effect relationship between proteasome impairment and interferonopathy onset. The purpose of this present review is therefore to discuss the possible role the UPR in the pathogenesis of PRAAS. We will particularly focus on pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling cascade is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets.
Proteostasis Perturbations and Their Roles in Causing Sterile Inflammation and Autoinflammatory Diseases
AbstractProteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or degradation. Over the last two decades, an increasing number of disorders caused by proteostasis perturbations have been identified. Depending on their molecular etiology, such diseases may be classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most-if not all-of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses. In this review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and summarize current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide insights into the complex and multiple facets of sterile inflammation.
Pediatric Hematology/Oncology and Immunopathology · 2019 · 3 citations · open access
Clinical case of proteasome-associated autoinflammatory syndrome-2 (PRAAS2)
AbstractThis article describes clinical case of a child with proteasome-associated autoinflammatory syndrome-2 (PRAAS2). First two cases in unrelated boys were described in July, 2018 by M. Cecilia Poli, Frederic Ebstein. We describe another case of PRAAS2. Mutations of the POMP-gene underlie PRAAS2 pathogenesis, causing defects of the POMP protein which plays important role in proteasomes maturation and leads to the clinical symptoms observed in three described cases. We also provide a short PRAAS2 background description, as well as key pathogenesis components, clinical findings description and analysis of three known PRAAS2 cases. Parents gave their consent to use personal data, including photos for clinical research and publications.
BORIS (University Library Bern) · 2020 · 1 citations · open access
[Pathophysiology of autoinflammatory dermatoses].
AbstractAutoinflammation leads to inflammation that mostly occurs without any clinically obvious reason. It can be so severe that organ damage with relevant tissue damage occurs. Inflammasomes are the drivers of autoinflammation. Although IL‑1 beta and the inflammasomes as its critical regulators are very important in autoinflammation, not all patients respond to inhibition of this signalling pathway. Several autoinflammatory diseases were associated with mutations in proteasome-immunoproteasome components. Autoinflammatory diseases caused by highly relevant genetic variants are mostly hereditary. Usually in childhood but not always. The coming years will show whether inflammatory dermatoses will be increasingly treated with suppression of the innate immune system in addition to inhibition of adaptive immunity.
Double-Edged Sword of Novel Anti-Cancer Treatment: Proteasome Inhibition in the Growth Plate Causes Impairment of Longitudinal Bone Growth
AbstractLongitudinal bone growth is a complex and tightly regulated process. A precise balance between proliferation, differentiation and cell death in growth plate chondrocytes is a key to normal bone growth in children. Indeed, decrease in proliferation/differentiation and increase in undesired cell death in growth plate cartilage are directly associated with impaired bone growth. Proteasome inhibitors are currently undergoing phase I and II clinical trials to evaluate their efficacy in the treatment of various childhood cancers. Effects of proteasome inhibitors on bone growth in children have not yet been reported. However, recent preclinical observations suggest that proteasome inhibitors may selectively target essential cell populations in growth plate cartilage, causing significant growth failure; an effect associated with increased apoptosis and decreased proliferation of chondrocytes. The observed effects on apoptosis and proliferation in growth plate chondrocytes appear to be mediated by several proteins including p53, apoptosis inducing factor (AIF), caspases, NF-κB and β-catenine. These observations could have important implications for the use of proteasome inhibitors in the treatment of childhood diseases. Keywords: Growth Plate, chondrocytes, bone, Apoptosis, proteasome inhibitors, Autophagy, cell death, apoptosis inducing factor (AIF), bortezomib, anti-cancer agents
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
