Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Proteasome-Associated Autoinflammatory Syndrome. Core disease mechanisms,...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Dysfunctional immunoproteasomes in autoinflammatory diseases

• Authors: H. Arimochi, Yuki Sasaki, A. Kitamura, K. Yasutomo
• Year: 2016
• Venue: Inflammation and Regeneration
• URL: https://www.semanticscholar.org/paper/f8ac8f6a0b7ab08ecd814880c28ff8dfd1395a11
• DOI: 10.1186/s41232-016-0011-8
• PMID: 29259686
• PMCID: 5721717
• Citations: 9
• Summary: Analysis of causal gene mutations, assessment of patients’ phenotypic changes, and appropriate animal models will be indispensable for clarifying the underlying mechanisms responsible for the development of autoinflammatory syndromes and establishing curative approaches.
• Evidence snippets:
• Snippet 1 (score: 0.579) > Improvements in genotyping efficiency, sequencing technology, and statistical methodology have made it possible for researchers to identify specific gene mutations associated with autoinflammatory syndromes. Some mutations and polymorphisms connected to dysregulated proteasome syndromes have been reported, but the functional consequences of genetic variations are not fully understood. To increase our understanding of the pathophysiology of these diseases, basic and advanced studies with tissues from patients and genetically modified animals will be required to determine how the mutations affect cellular physiology and proteasome function. Analysis of causal gene mutations, the subsequent phenotypic changes in autoinflammatory syndrome patients, and establishment of a proper animal model for these diseases will be indispensable to clarify the mechanisms of autoinflammatory syndrome development and to develop cures for these diseases.

[2] Role of Proteasomes in Inflammation

• Authors: Carl Christoph Goetzke, F. Ebstein, T. Kallinich
• Year: 2021
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/38db69eac24c0c546e0d313ab2f3301c6f007124
• DOI: 10.3390/jcm10081783
• PMID: 33923887
• PMCID: 8072576
• Citations: 71
• Influential citations: 1
• Summary: A light is cast on the different clinical aspects of proteasomal activity in human disease and the currently studied therapeutic approaches are summarized.
• Evidence snippets:
• Snippet 1 (score: 0.523) > The ubiquitin–proteasome system (UPS) is involved in multiple cellular functions including the regulation of protein homeostasis, major histocompatibility (MHC) class I antigen processing, cell cycle proliferation and signaling. In humans, proteasome loss-of-function mutations result in autoinflammation dominated by a prominent type I interferon (IFN) gene signature. These genomic alterations typically cause the development of proteasome-associated autoinflammatory syndromes (PRAAS) by impairing proteasome activity and perturbing protein homeostasis. However, an abnormal increased proteasomal activity can also be found in other human inflammatory diseases. In this review, we cast a light on the different clinical aspects of proteasomal activity in human disease and summarize the currently studied therapeutic approaches.

[3] Disorders of ubiquitylation: unchained inflammation

• Authors: D. Beck, Achim Werner, D. Kastner, I. Aksentijevich
• Year: 2022
• Venue: Nature Reviews. Rheumatology
• URL: https://www.semanticscholar.org/paper/f70d358e861f27cf6e94321d108ac07c274b9df4
• DOI: 10.1038/s41584-022-00778-4
• PMID: 35523963
• PMCID: 9075716
• Citations: 94
• Summary: The authors describe the molecular pathogenesis of disorders of ubiquitylation that result in innate immune overactivation and systemic autoinflammatory disease and suggest novel treatment avenues.
• Evidence snippets:
• Snippet 1 (score: 0.482) > Dysregulation of ubiquitylation is linked to many distinct disorders of recurrent systemic inflammation that are collectively known as systemic autoinflammatory diseases (SAIDs) 26 . Studies of patients with SAIDs and of animal models that phenocopy these conditions have revealed basic mechanisms related to innate immunity that are widely applicable across many different disease states 9 . SAIDs are caused by genetic mutations that lead to enhanced or constitutive inflammation, either gain-of-function mutations in activators or sensors of immune responses (such as NLRP3, mutation of which results in cryopyrin-associated periodic syndrome) 27,28 , or loss-of-function mutations in inflammatory repressors (such as IL1RN, mutation of which results in deficiency of IL-1 receptor antagonist) 29,30 . Identification of the molecular causes of such diseases is important to enable correct clinical diagnosis and selection of targeted therapies. > SAIDs can be categorized according to a number of parameters, such as clinical manifestation 31 , genetics 32 and molecular pathogenesis 33 ; however, in this Review, we focus on the biochemical pathways of ubiquitylation in autoinflammatory diseases as a defining feature. Depending on which step in the ubiquitylation hierarchy is compromised, dysregulation of ubiquitylation can directly affect a particular signalling pathway (for example, through mutations affecting E3 ligases and deubiquitylases) that will ultimately result in activation of cellular stress responses, or it can cause general cellular stress as an immediate consequence (for example, through mutations affecting E1 enzymes or the proteasome). We focus here on existing data from human genetic diseases and supporting evidence from relevant model organisms to review the current understanding of the pathology and molecular basis of associated pheno types. Strikingly, defects in general components of the ubiquitin-proteasome system (UPS) and in highly substrate-specific ubiquitin ligation and deconjugation enzymes can lead to overlapping clinical presentations, suggesting commonalities that are not apparent at the level of known molecular aetiology. Given the highly targetable nature of the ubiquitin pathway 34 , conceptually connecting these diseases may be important for designing rational therapeutics across diagnoses.

[4] Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases

• Authors: I. Figueras-Nart, J. Mascaró, X. Solanich, J. Hernández-Rodríguez
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/a35ef549aec6f85304e8a71d2e547781e9ae64c7
• DOI: 10.3389/fimmu.2019.02448
• PMID: 31736939
• PMCID: 6828938
• Citations: 43
• Influential citations: 1
• Summary: This review intends to provide clinical and histopathological knowledge about cutaneous involvement in monogenic autoinflammatory diseases with cutaneous expression by using this classification.
• Evidence snippets:
• Snippet 1 (score: 0.481) > IFN interacts with its surface receptor IFN-α and induces the STAT pathway, which induces the transcription of IFN genes and promotes antiviral activity. In addition, proteins regulating the synthesis or degradation of nucleic acids such as TREX1, SAMHDI, and RNase H2 play an important role in IFN genes activation. Immunoproteasomes are protein complexes that degrade ubiquitinated intracellular proteins and are implicated in cellular stress responses, as well as activating IFN (11,13). > IL-1-mediated and IFN type I-mediated autoinflammatory diseases and their main genetic and pathogenic aspects are illustrated in Figure 1. > Over time, different classifications of monogenic autoinflammatory diseases have been proposed according to molecular and etiopathogenic mechanisms involved (11,15), type of inheritance (16), genetic background and clinical presentation (17,18). Apart from FMF and CAPS, other wellcharacterized monogenic inflammasomopathies comprise TNF receptor-associated periodic syndrome (TRAPS), hyper-IgD syndrome (HIDS), pediatric granulomatous arthritis (Blau syndrome and early onset sarcoidosis), pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), deficiency of IL-1 receptor antagonist (DIRA) and deficiency of interkeukin-36 receptor antagonist (DITRA). All the monogenic autoinflammatory diseases covered in this review classified according to the major pathogenic mechanism are listed in Table 1. > Polygenic or multifactorial autoinflammatory diseases are defined as complex systemic disorders sharing an autoinflammatory and sometimes autoimmune background, with an unknown genetic cause.

[5] Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24

• Authors: Sophia Davidson, Chien-Hsiung Yu, A. Steiner, F. Ebstein, Paul J. Baker et al.
• Year: 2022
• Venue: Science Immunology
• URL: https://www.semanticscholar.org/paper/b6da201d281b7d44682058acacd86909d8bf4747
• DOI: 10.1126/sciimmunol.abi6763
• PMID: 35148201
• Citations: 49
• Influential citations: 2
• Summary: Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon and NF-κB signaling and protein kinase R (PKR) is identified as an innate immune sensor for proteotoxic stress, causing inflammation observed in the disease PRAAS.
• Evidence snippets:
• Snippet 1 (score: 0.477) > Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor–induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum–associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS. Description Under conditions of proteasome dysfunction, IL-24 accumulated in the cytosol and triggered PKR-mediated inflammation. Stress leads to IL-24 danger It is unclear how proteasome dysfunction leads to inflammation in patients with proteasome-associated autoinflammatory syndrome (PRAAS). Davidson et al. used multiple knockout cell lines, knockout mice, and primary PRAAS patient samples to identify that protein kinase R (PKR) activation drove elevated innate immune responses. Activation of PKR was induced by the cytoplasmic

[6] Targeted Drugs for Cancer Therapy: Small Molecules and Monoclonal Antibodies

• Authors: B. Baldo, N. Pham
• Year: 2020
• Venue: Drug Allergy
• URL: https://www.semanticscholar.org/paper/8d0fa01c6728505dbf2d557c8fb21703bdd9d376
• DOI: 10.1007/978-3-030-51740-3_14
• PMCID: 7979054
• Citations: 3
• Summary: Severe infusion reactions provoked by mAbs can resemble anaphylaxis, cytokine-release syndrome, infusion, and type I allergic reactions, while tumor lysis syndrome, unlike CRS, is easy to distinguish from type I immediate reactions.
• Evidence snippets:
• Snippet 1 (score: 0.468) > Fig. 14.7 Diagrammatic representation of the proteasome and its role in protein degradation via the ubiquitinproteasome pathway. After being tagged with ubiquitin and unfolded for degradation on the 19S regulatory particles which aid the opening of a proteolytic gate in the 20S core, proteins are degraded into small peptides in the barrel-shaped core where β1 caspase-, β2 trypsin-, and β5 chymotrypsin-like activities reside. Regulatory particles are composed of a base (dark blue), lid (yellow-brown), and so-called arm (pink). The 20S proteolytic core may be capped at one or both ends by a 19S regulatory particle. > Proteasomes are thus referred to as single-capped (sedimentation coefficient ~26S) or double-capped (~30S). In the literature, the term 26S proteasome is often used incorrectly when referring to the double-capped form. > The double-capped complex is thought to be the functional proteasome unit in the cell a stimulant in attempts to understand the molecular mechanisms underlying its clinical effectiveness and identifying new drugs acting on the same pathway. > Gastrointestinal symptoms, thrombocytopenia, neutropenia, peripheral neuropathy, neuropathic pain, and fatigue are the most common side effects of bortezomib, and adverse cutaneous reactions to the drug are numerous (Table 14.1). Rash (often pruritic) is frequently reported in more than 10% of patients (an incidence of 8-18% has been stated), and pruritus, erythema, urticaria, periorbital edema, and eczema are commonly seen. Bortezomib has been associated with cases of drug-induced Sweet's syndrome-like reactions (Fig. 14.9) or acute febrile neutrophilic dermatosis, a rare variant of this uncommon skin disease characterized by fever, an elevated neutrophil count, and erythematous lesions infiltrated by neutrophils.

[7] Ubiquitin-proteasome system dysregulation in FAM111B-related poikiloderma and phenotypic spectrum expansion: new case reports and long-term follow-up

• Authors: Virginie Vignard, M. Maillasson, Anne Bigot, S. Küry, T. Besnard et al.
• Year: 2025
• Venue: eBioMedicine
• URL: https://www.semanticscholar.org/paper/772c41073c92ba0c7664b3d7603425930c0ccc93
• DOI: 10.1016/j.ebiom.2025.105864
• PMID: 40840166
• PMCID: 12396287
• Summary: A dysfunctional UPS is highlighted as a potential central driver of POIKTMP's molecular pathogenesis, presenting promising therapeutic avenues, and Notably, variants clustering within the D-box domain of FAM111B protein tend to present a more severe phenotype.
• Evidence snippets:
• Snippet 1 (score: 0.463) > Our work expanded the cellular phenotype of POIKTMP by introducing protein homoeostasis disruption to its repertoire. In addition, FAM111B variants were associated with the acquisition of specific type I IFN gene (Fig. 10 and Supplementary Fig. S7) and proteomic (Table 2) signatures in POIKTMP cells, a well-known autoinflammatory feature of disorders caused by protein homoeostasis perturbations. 47,48,66 lthough we do not fully understand the biological relevance of these responses in this context, the fact that IFN induces immunoproteasomes and proteasome activators [67][68][69] suggested that they may be part of a compensatory mechanism to enhance proteasome function. > Most importantly, our data indicated that the cellular phenotype of POIKTMP shared features with neurological disorders involving protein homoeostasis perturbations. These disorders notably include late-onset neurodegenerative disorders such as Parkinson disease and Alzheimer disease, 70,71 as well as the more recently described early-onset neurodevelopmental proteasomopathies caused by loss-of-function variants in proteasomal genes. 47,72,73 This concept might initially pique curiosity, especially when considering that POIKTMP patients typically do not exhibit neurological manifestations. 30 However, this contrast can be explained by the low expression of FAM111B in the brain compared to higher expression in other organs such as the skin, pancreas, and gastrointestinal tract. 74 One should emphasize that disruptions in protein homoeostasis are also a hallmark of specific autoinflammatory disorders, particularly chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CAN-DLE), also known as proteasome-associated autoinflammatory syndromes [PRAAS]. 6][77] This raises the question of whether therapeutic approaches used for CANDLE/PRAAS, such as JAK inhibitors for managing dermatological symptoms, 78 could potentially be extended to POIKTMP.

[8] Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)

• Authors: F. Ebstein, María Cecilia Poli Harlowe, Maja Studencka-Turski, E. Krüger
• Year: 2019
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/8cacb0ea1cb1fd2761e742520c656faebf95e24b
• DOI: 10.3389/fimmu.2019.02756
• PMID: 31827472
• PMCID: 6890838
• Citations: 72
• Summary: The possible role of the UPR in the pathogenesis of PRAAS is discussed and pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α, and TCF11/Nrf1 which undergo activation under proteasome inhibition are focused on.
• Evidence snippets:
• Snippet 1 (score: 0.461) > Type 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 of 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 casacades is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets.

[9] Type I Interferonopathies in Children: An Overview

• Authors: D. M. d’Angelo, Paola Di Filippo, L. Breda, F. Chiarelli
• Year: 2021
• Venue: Frontiers in Pediatrics
• URL: https://www.semanticscholar.org/paper/5931ebb81ed9144967b1546fc3ccfec35582479e
• DOI: 10.3389/fped.2021.631329
• PMID: 33869112
• PMCID: 8044321
• Citations: 66
• Influential citations: 3
• Summary: The characterization of interferonopathy molecular pathogenetic mechanisms is allowing important steps forward in other immune dysregulation diseases, such as systemic lupus erythematosus and inflammatory myositis, implementing the opportunity of a more effective target therapy.
• Evidence snippets:
• Snippet 1 (score: 0.456) > PRAAS are a heterogeneous group of interferonopathies caused by inherited loss-of-function mutations in genes encoding proteasome subunits of 20S core particles such as PSMB8, PSMB9, PSMB7, and PSMA3 or proteasome chaperone factors such as POMP and PSMG2 (Table 1). These mutations lead to a failure of proteasome complex formation, causing an alteration of intracellular protein homeostasis and the accumulation of ubiquitinated proteins (2,(89)(90)(91)(92). The underlying molecular mechanisms that link this alteration to the activation of the IFN pathway are not yet fully understood. Recently, new insights came from the unfolded protein response (UPR), which originated in response to an accumulation of misfolded proteins in the ER (ER stress). Indeed, defective proteasome compromises the ER-associated protein degradation, resulting in an accumulation of misfolded ER proteins in the lumen. This alteration is determined by three intra ER membrane-resident proteins, in particular the inositol-requiring enzyme 1α/β (IRE1), with subsequent activation of a signal pathway that allows NF-κB activation and IRF3 factor transcription, leading to a IFNdepending inflammation (92,93). PRAAS include the Japanese autoinflammatory syndrome with lipodystrophy (JASL) and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) syndromes (2). Common clinical features are the presence of pernio-like purplish nodular lesions (neutrophilic dermatosis), panniculitis with progressive lipodystrophy and muscle atrophy, and joint contractures with extremity deformity. Hepatosplenomegaly and hypochromic or hemolytic anemia were also reported. An early metabolic syndrome, with systemic hypertension and dyslipidemia, occurs in 40-80% of patients (89)(90)(91)(92). Proteasome defects were also associated with neurologic diseases.

[10] Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

• Authors: M. Di Rosa, C. Giallongo, A. Romano, D. Tibullo, G. Li Volti et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/708b84a11830fc7dfc63b28cebc5b6fc5dd8861b
• DOI: 10.3390/ijms21082926
• PMID: 32331228
• PMCID: 7216198
• Citations: 11
• Summary: The results demonstrate that IPs and IFNG pathways could be involved in PMF disease and in particular in patients carrying the JAK2V617F mutation.
• Evidence snippets:
• Snippet 1 (score: 0.449) > Clinical benefits of RUX are partially derived from the reduction of inflammatory cytokines, with an early relief of clinical symptoms and reduction of spleen size after 4 weeks post-treatment [12,13]. Only in a few cases the drug reverts bone marrow fibrosis or reduces the allele burden [14], suggesting that other intracellular signaling in the neoplastic clone or in the host-tumor interaction can affect the clinical course of PMF. > Several papers have shown evidence of a dysregulation of the immune system in the MPNs. PMF is considered as an inflammatory disease where the higher cytokine secretion creates a pro-inflammatory milieu influencing the immune system [15]. It has been demonstrated that several immune defects are principally associated with the presence/absence of the JAK2 V617F mutation [16,17]. Overall, these anomalies could contribute to the development of an immune deficiency state with the potential to promote immune evasion, cancer progression and increased susceptibility to infections [18]. Furthermore, a better understanding of immune biology in the context of PMF would be important for the design of new therapies for PMF. > In eukaryotic cells, the proteasomes (c-20S) are ubiquitously-expressed cellular proteases involved in the degradation of intracellular oxidized proteins following an oxidative insult, through an ATP-independent mechanism [19]. Being ubiquitously expressed, these proteins represent a potential pharmacological target even though with several limitations [20]. To this regard, Bortezomib, a potent and clinically relevant proteasome inhibitor, is intermittently used for multiple myeloma treatment (MM) [21,22] and other inflammatory disease [23][24][25], in order to limit toxic effects [26]. In cells of hematopoietic origins, the classical proteasome is replaced by a different proteasome with an immunological role called immunoproteasome (IPs) [27].

[11] Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

• Authors: Saika Sharmeen, L. Christopher‐Stine, Joann N. Salvemini, P. Gorevic, R. Clark et al.
• Year: 2024
• Venue: Rheumatology and Immunology Research
• URL: https://www.semanticscholar.org/paper/996899888fef5b2dd60f264bb0a1d25a784c1ce7
• DOI: 10.1515/rir-2024-0005
• PMID: 38571935
• PMCID: 10985708
• Citations: 1
• Summary: Accumulating data supports a major role of the innate immune system and a similar cytokine profile in SAID patients and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors.
• Evidence snippets:
• Snippet 1 (score: 0.448) > We believe that further genetic profiling will be useful in the context of an autoinflammatory disease gene panel to cover both high and low penetrance variants.This may be necessary to identify genetic variants associated with SAIDs in a subgroup of DM or ADM patients. > The central hypothesis of mechanisms underlying SAIDs is abnormal innate immune response.Mechanisms in SAIDs are complex and heterogenous, depending on individual disease categories.For example, for hereditary recurrent fever syndromes and NOD-like receptor (NLR) associated SAIDs (FMF, CAPS, NLRP12-AID), genetic variations, inflammasomes and aberrant cytokines such as IL-1β, IL-8 and IL-18 contribute to these diseases. [3]NOD2-associated diseases, such as Crohn's disease, Blau syndrome and YAOS are associated with NOD2 mutations that result in abnormal NOD2 activation of RIP2, NF-κB, MAPK, Caspase-1 pathways, as well as cytokine production like IL-1, IL-8 and IL-6. [38]everal new complex clinical autoinflammatory syndromes include systemic inflammation, panniculitis, and myositis due to proteasome defects (PRAAS/CANDLE), vasculopathy, vasculitis, and interstitial lung disease with STING hyperactivity (SAVI), and subacute encephalomyelitis with cerebral calcifications and white matter disease due to cytosolic nucleotide dysregulation (AGS).These diseases are caused by mutations leading to chronic type I interferon (IFN) production as inflammatory mediators that cause autoinflammatory phenotypes. [39]terestingly, there are reports to link inflammasome with DM.

[12] Protein Homeostasis, Aging and Alzheimer’s Disease

• Authors: T. Morawe, C. Hiebel, Andreas Kern, C. Behl
• Year: 2012
• Venue: Molecular Neurobiology
• URL: https://www.semanticscholar.org/paper/3d06e94f0749ebce0384b7e17a16a242edd60392
• DOI: 10.1007/s12035-012-8246-0
• Summary: Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis.
• Evidence snippets:
• Snippet 1 (score: 0.445) > There is quite some evidence that in AD, the proteostasis network is impaired. Based on pathological analysis, AD mouse models, in vitro and cellular investigations a molecular link between chaperones, the ubiquitin-proteasome system, autophagy pathways and pathogenetic mechanisms of AD can be suggested. Deregulation and changes of chaperones and proteasome activity might have serious implications for aging as well as for age-associated diseases. Autophagy pathways are key mechanisms and of vital importance for cellular function and, especially, for cell survival under adverse conditions. Consequently, an effect of proteostasis control on neurodegeneration or, vice versa, of neurodegeneration on proteostasis is reasonable. As with other pathomechanisms that are investigated in the search for the cause of AD, it is still open whether an impairment of proteostasis is an upstream or downstream event during AD onset and progression. Experimental approaches employing mouse models clearly demonstrate that stabilization or induction of proteostasis can be neuroprotective. Whether this can be translated into the human condition and, most importantly, whether supporting proteome integrity can be a real target for pharmacological intervention for the prevention and treatment of AD is currently still open. Also, one has to consider that, e.g. the stimulation of general autophagy may in the long term lead to the stimulation of proliferation of non-neuronal cells, eventually resulting in tumor formation. Indeed, a permanent autophagy induction is known as one cellular mechanism that promotes the escape of cells from proliferation control. As beneficial it may be to support autophagy in post-mitotic neurons that are confronted with disturbed proteostasis and an impairment of proteasome function, this stimulation should target specific autophagy pathways, such as selective chaperone-mediated macroautophagy involved in the degradation of disease-associated protein aggregation. Although there are obviously still many questions to be answered to understand the role of proteostasis in AD (and also in other age-associated neurodegenerative disorders), it is a big step forward in AD research to consider a possible role of pathogenetic pathways that are not directly linked to the usual suspects Aβ and Tau.

[13] Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology

• Authors: Simona N Shirley, Abigail E. Watson, Nabiha Yusuf
• Year: 2024
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/a1e66ada3d9b0a74379022fc47ec053e5fe1503b
• DOI: 10.3390/ijms251810152
• PMID: 39337637
• PMCID: 11431851
• Citations: 37
• Summary: Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease.
• Evidence snippets:
• Snippet 1 (score: 0.445) > Deep within the core of all anatomic and clinical pathology, cellular components and their complex interactions form the basis of disease. Thus, the secret code to understanding and managing skin disease lies in the land of submicroscopic changes and the miniscule, yet majorly important mechanisms of the body's molecules. Molecular pathology, or the study of disease through the examination of intracellular and extracellular constituents such as proteins and nucleic acids, underpins much of current knowledge regarding the causes of skin disease and the effective targets for therapeutic strategies. Every day, the scientific community's appreciation for molecular sources of skin disease expands as new studies emerge. This literature review, which examines the inflammatory mechanisms of skin disease at a molecular level, seeks to highlight current areas of interest in the field and exciting new advancements in the community's understanding of dermatopathology. After introducing each relevant component of pathogenic inflammation and identifying the specific mechanisms most widely addressed in the recent literature, the details of each process as they apply to individual skin diseases will be discussed. Whether they are classified as autoimmune, autoinflammatory, or both autoimmune and autoinflammatory, all disease processes included in the review involve pathogenic inflammatory mechanisms in the skin. Importantly, all included diseases also represent potential candidates for the emerging avenues of anti-inflammatory therapies mentioned in the review.

[14] Induced pluripotent stem cells representing Nakajo-Nishimura syndrome

• Authors: N. Kanazawa, Fumiko Honda-Ozaki, M. Saito
• Year: 2019
• Venue: Inflammation and Regeneration
• URL: https://www.semanticscholar.org/paper/807e8addb520e998f152fb2aedfdb67b67361611
• DOI: 10.1186/s41232-019-0099-8
• PMID: 31143302
• PMCID: 6532143
• Citations: 5
• Summary: The results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.
• Evidence snippets:
• Snippet 1 (score: 0.443) > Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct homozygous mutation in the PSMB8 gene encoding an inducible β5i subunit of the immunoproteasome. Although it is considered that immunoproteasome dysfunction causes cellular stress and contributes to the production of inflammatory cytokines and chemokines, its detailed mechanism is still unknown. On the other hand, hereditary autoinflammatory diseases are considered as a good target for the analyses using induced pluripotent stem cells, whose differentiation systems to the innate immune cells such as neutrophils and monocytes have been established. Therefore, to elucidate the pathogenesis of Nakajo-Nishimura syndrome, we attempted in vitro disease modeling using patient-derived induced pluripotent stem cells. For analyses, isogenic control cells in which the responsible mutation was repaired and another pair of healthy embryonic stem cells and isogenic mutant cells in which the same mutation was introduced had also been prepared with genetic engineering. By comparing a pair of isogenic cells with the wild-type and the mutant PSMB8 gene after differentiation into monocytes and immortalization to synchronize their differentiation stages, the reduction of immunoproteasome enzyme activity and increased cytokine and chemokine production in the mutant cells without stimulation or with interferon-γ plus tumor necrosis factor-α stimulation were observed, and therefore, the autoinflammatory phenotype was successfully reproduced. Decreased cytokine production was observed by the addition of antioxidants as well as inhibitors for Janus kinase and p38-mitogen-activated protein kinase. At the same time, the increased production of reactive oxygen species and phosphorylation of both signal transducers and activator of transcription 1 and p38-mitogen-activated protein kinase were detected without stimulation. Notably, an antioxidant specifically decreased the constitutive phosphorylation of signal transducers and activator of transcription 1. These results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakaj

[15] Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease

• Authors: F. Caso, P. Galozzi, L. Costa, P. Sfriso, L. Cantarini et al.
• Year: 2015
• Venue: RMD Open
• URL: https://www.semanticscholar.org/paper/a04ee83fc3b9dbf5ade58ddb8c35a2c5e1a63479
• DOI: 10.1136/rmdopen-2015-000097
• PMID: 26509073
• PMCID: 4612691
• Citations: 136
• Influential citations: 3
• Summary: Genetic and clinical aspects of Blau syndrome and early-onset sarcoidosis are described, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge.
• Evidence snippets:
• Snippet 1 (score: 0.442) > In past years, the recognition of different mutations in genes involved in the regulation of inflammatory and apoptotic cellular mechanisms has allowed the characterisation of monogenic autoinflammatory syndromes. 1 Despite their genetic and clinical heterogeneity, the common starting mechanism of these diseases has been identified in the dysfunction of innate immunity and inflammasome processes. 1 Physiologically, the inflammasome represents a multiprotein cytoplasmatic platform that, when assembled, following a proinflammatory trigger, activates caspases, which convert prointerleukin (IL)-1β into its active form, IL-1β, a key molecule of inflammation and innate immunity. 2 In monogenic autoinflammatory syndromes, a genetic-driven erroneous assembly of the inflammasome leads mainly to an overstated increase in IL-1β with an aberrant inflammatory response. 2 Recurrence of the inflammatory attacks are the main temporal characteristics of these diseases, thus reflecting their spontaneous and unbalanced nature. 1 2 Although the knowledge of IL-1β and inflammasome mechanisms represents Key messages ▸ Blau syndrome (BS) and early-onset sarcoidosis (EOS) caused by mutations in the CARD15/ NOD2 gene, represent familial and sporadic phenotypes of the same non-caseating granulomatous inflammatory disease. ▸ The CARD15/NOD2 gene has also been identified as one of the genes linked to susceptibility to Crohn's disease (CD). ▸ Other substitutions in the CARD15/NOD2 gene have also been found in a recently described disorder, called NOD2-associated autoinflammatory disease (NAID). ▸ The improvement of knowledge in molecular mechanisms and diagnosis of these diseases can represent an important breakthrough for improving their outcomes. > the major conceptual progress in the autoinflammatory processes, the recognition of various genetic backgrounds has been useful to classify different groups of autoinflammatory disorders. 1 Among these diseases, two rare non-caseating granulomatosis, Blau syndrome (BS) and early-onset sarcoidosis (EOS), caused by sequence variants in CARD15/NOD

[16] The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

• Authors: F. Moghaddas, S. Masters
• Year: 2018
• Venue: Clinical Science (London, England : 1979)
• URL: https://www.semanticscholar.org/paper/eaeea6f5f6c692b8ba8eb598f992134544b1f611
• DOI: 10.1042/CS20171498
• PMID: 30185613
• PMCID: 6123071
• Citations: 23
• Influential citations: 1
• Summary: This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models.
• Evidence snippets:
• Snippet 1 (score: 0.440) > tokine profile, but little is known about the steps that lead to this alteration. Proteasome-associated autoinflammatory syndrome (PRAAS) is an autosomal recessive autoinflammatory disorder that encompasses conditions previously considered distinct entities: Nakajo-Nishimura syndrome (NKJO), joint contractures, muscular atrophy, microcytic anaemia, and panniculitis-induced lipodystrophy syndrome (JMPS), as well as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Three publications identified mutations in PSMB8, the β5i catalytic component of the immunoproteasome, as the cause of disease [55][56][57]. Individuals with homozygous loss of function mutations in PSMB8 experienced spontaneous febrile episodes with features of muscle weakness, lipodystrophy as well as neutrophilic and lymphocytic infiltrative skin nodules and evidence of cerebral calcification [55][56][57]. Homozygous mutations were associated with poor proteasome assembly as well as reduced chymotrypsin-like activity and accumulation of ubiquitinated proteins in either Epstein-Barr virus (EBV)-transformed B cells or immortalised lymphoblastoid cell lines from cases [55][56][57]. In these early papers, increased serum IL-6 was noted in all cases, but the role of IFN was only identified later [58]. Liu et al. noted an almost 80-fold increase in IFN-γ-inducible protein 10 (IP-10) in cases compared with healthy controls and individuals with CAPS, prompting whole blood microarray analysis to determine the gene signature of these cases. The IFN pathway was the most differentially regulated pathway in individuals with PRAAS, further supported by stronger STAT1 phosphorylation in response to IFN-γ stimulation of monocytes when compared with healthy controls. These authors also highlighted cases with the clinical phenotype of PRAAS without PSMB8 mutations, later explored by Goldbach-Mansky et al. [59].

[17] Ventilator-induced diaphragmatic dysfunction: pathophysiology, monitoring and advances in potential treatment and prevention

• Authors: Wei Fu, L. Guan, Qi Liu, Zhefan Xie, Junting You et al.
• Year: 2025
• Venue: European Respiratory Review
• URL: https://www.semanticscholar.org/paper/5c42bb3cd0f8f598a75e0484ea389ece3aeeab49
• DOI: 10.1183/16000617.0069-2025
• PMID: 41062169
• PMCID: 12505153
• Citations: 5
• Summary: The epidemiology and pathophysiological mechanisms of VIDD and advances in potential treatment and prevention are summarised.
• Evidence snippets:
• Snippet 1 (score: 0.431) > Mechanical ventilation is a life-saving method for those critically ill patients with acute or chronic respiratory failure without assistance. However, even short-term mechanical ventilation can lead to alterations in the fibrous structure and reduced contraction force of the diaphragm, which is defined as ventilator-induced diaphragmatic dysfunction (VIDD). This condition is associated with various risks of adverse clinical outcomes. Research on mechanical ventilation-related respiratory mechanics helps us to understand the macroscopic myotrauma mechanisms of VIDD. Ongoing clinical trials into comprehensive management strategies for lung- and diaphragm-protective ventilation are continually refining respiratory therapy protocols in clinical practice. Although the cellular and molecular mechanisms are not fully defined, pathways involving mitochondrial oxidative stress have been identified as key contributors to disease progression, leading to both accelerated proteolysis and depressed protein synthesis. Additionally, research on the ubiquitin–proteasome pathway, lysosomal autophagy, calpain, caspase-3 and dysfunction of the ryanodine receptor-1 pathway is enhancing our understanding of the downstream mechanisms involved. Promising interventions based on these findings have yielded hopeful results in animal models for preventing VIDD. This review summarises the epidemiology and pathophysiological mechanisms of VIDD and advances in potential treatment and prevention. Shareable abstract Mitochondrial oxidative stress is a key contributor to VIDD. Inhibition of protein synthesis and enhanced degradation are important mechanisms for VIDD. Drugs and optimised mechanical ventilation continue to advance the goal of diaphragm protection. https://bit.ly/3IcJtri

[18] Editorial: Autoinflammatory Diseases: From Genes to Bedside

• Authors: I. Aksentijevich, A. Soriano, J. Hernández-Rodríguez
• Year: 2020
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/9fbb99451e1a052657812382bbf20617ae9c74d4
• DOI: 10.3389/fimmu.2020.01177
• PMID: 32636839
• PMCID: 7318105
• Citations: 9
• Summary: This poster presents a poster presented at the 2016 International Conference of the American Academy of Pathologists on Autoinflammatory Diseases and Vasculitis to highlight the need to understand more fully the mechanism behind inflammation and its role in disease progression.
• Evidence snippets:
• Snippet 1 (score: 0.428) > Witnessing these developments has been incredibly rewarding for those of us in the field and it will be exciting to see where it goes from here. > In the present issue of Frontiers in Immunology, "Autoinflammatory diseases: from genes to bedside, " the first monographic issue about autoinflammatory diseases, several investigators have contributed with original and review articles covering genetic, pathogenic, epigenetic, clinical and therapeutic aspects of different autoinflammatory conditions. > The "genes" part of the topic explores relevant genetic, pathogenic and epigenetic mechanisms implicated in autoinflammatory diseases. Martorana et al.. review the most common mutations and the evidences of genotype/phenotype correlations of the main monogenic autoinflammatory diseases. The role of NLRP3 and pyrin inflammasomes in the pathogenesis of CAPS, and FMF and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND), respectively, has been addressed by de Torre-Minguela et al.. Aksentijevich and Zhou describe the latest advances on the pathogenic mechanisms of ubiquitinopathies, a new category of autoinflammatory diseases involved in the NF-κB pathway, which include linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. Carta et al.. propose two different pathways of inducing abnormal IL-1β production in autoinflammatory diseases depending on the cell type affected, in which the authors postulate that professional inflammatory cells would cause a direct inflammatory response and non-immune cells may participate indirectly in the inflammatory cascade by releasing stress signals that trigger and propagate inflammation. In the same sense, Gül reviews the concept of autoinflammation and uses it for monogenic and polygenic autoinflammatory diseases associated with seemingly unprovoked inflammatory episodes mediated mainly by the innate immune system. In addition, Gül also proposes and expands nomenclature by using the concept of "hyperinflammatory" state for those disorders characterized by episodes of exaggerated inflammatory response only when triggered by certain factors or situations.

[19] Trained Immunity Contribution to Autoimmune and Inflammatory Disorders

• Authors: S. C. Funes, M. Ríos, Ayleen Fernández-Fierro, M. S. Di Genaro, A. Kalergis
• Year: 2022
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/219297438808f2c483bdf5aea5c2e2f35ea096cf
• DOI: 10.3389/fimmu.2022.868343
• PMID: 35464438
• PMCID: 9028757
• Citations: 41
• Summary: The metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma are described, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.
• Evidence snippets:
• Snippet 1 (score: 0.426) > A critical pathogenetic mechanism in AIF diseases is the dysregulation of the inflammasomes, multiprotein cytoplasmic complexes relevant to innate immunity and inflammatory responses. The main components of inflammasomes are members of the NLR family that detect PAMPs or DAMPs and initiate inflammasome assembly. Thus is induced the proteolytic activation of caspase 1 or 11 and the cleavage and subsequent release of bioactive IL-1b, a key molecule of inflammation and innate immunity (115). Notably, mutations of genes encoding for the components of the proteins involved in the inflammasome (NLRP3) are implicated in the AIF called Cryopyrin-associated periodic syndromes (CAPS) (116). > On the other hand, some AIF diseases are caused by abnormalities of the ubiquitin-proteasome system (UPS), which regulates multiple cellular processes (117). Mutations that cause loss of UPS function in humans lead to a typical type I IFN gene signature and proteasome-associated autoinflammatory syndromes (PRAASs) (118). Although the causes of the induction of sterile inflammation in subjects with PRAAS are still unknown, it is believed that it could be associated with the propagation of endoplasmic reticulum (ER) stress (119). Proteasome defects are known to lead to the retention of misfolded proteins in the ER, leading to inflammation in a pathogen-free setting (120). Another recently described AIF disease related to UPS malfunction is VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (121). Myeloid lineage-restricted somatic mutations of UBA1 (a gene encoding the ubiquitin-activating enzyme 1) characterize VEXAS, leading to inflammation (121). Although the impact of trained immunity in these conditions is unknown to date, it could be assumed that stimuli that establish the capacity of a strengthened response by the innate system could be harmful in these systemic inflammatory diseases.

[20] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.416) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.