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Adenine Phosphoribosyltransferase Deficiency

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adenine Phosphoribosyltransferase Deficiency. Core disease mechanisms, mol...

2026-05-10
Asta MONDO:0013869 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adenine Phosphoribosyltransferase Deficiency. Core disease mechanisms, mol...

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

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy

  • Authors: Sigal Rencus-Lazar, Yasmin DeRowe, Hanaa Adsi, E. Gazit, Dana Laor
  • Year: 2019
  • Venue: Frontiers in Molecular Biosciences
  • URL: https://www.semanticscholar.org/paper/8080662b575308ff2b2bcc7704a060c8f04f5af6
  • DOI: 10.3389/fmolb.2019.00015
  • PMID: 30968029
  • PMCID: 6439353
  • Citations: 37
  • Influential citations: 2
  • Summary: Currently available yeast models of diverse amyloid-associated disorders of neurodegenerative disorders are described, as well as their impact on the understanding of disease mechanisms and contribution to future potential drug development.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Inborn error of metabolism (IEM) disorders result from mutations in genes encoding for various metabolic enzymes. Consequently, the corresponding metabolite substrate accumulates, leading to diverse symptoms (Ferreira et al., 2018). However, the molecular mechanisms underlying the development of the specific symptoms of each of these disorders in specific organs are still mostly unknown. Recently, a new paradigm for metabolite accumulation and their putative roles in metabolic disorders was established. Several amino acids and nucleobases, including adenine, have been shown to form archetypical nanofibrils, displaying amyloid-like properties, in vitro (Adler-Abramovich et al., 2012;Shaham-Niv et al., 2015). These amyloid-like structures were suggested to be associated with the pathology that underlies several genetic metabolic disorders, thus postulating IEM conditions to constitute yet another group of amyloid-associated disorders (Gazit, 2016). However, studies exploring the formation of amyloid-like assemblies by various metabolites were so far performed mostly in vitro. Hence, evidence for the role of metabolite assemblies in an in vivo model has been lacking. > Given the high degree of conservation of metabolic pathways across all branches of life, simple models can be established to study the devastating disorders observed upon metabolites accumulation. Thus, aiming to understand the biological relevance and consequences of this metabolite self-assembly, we set out to establish the first in vivo yeast model for studying adenine accumulation. In humans, inborn mutations in genes involved in the adenine salvage pathway can lead to the development of several metabolic disorders. Among these, mutations in adenine phosphoribosyltransferase (APRT) and adenosine deaminase (ADA) lead to APRT and ADA deficiency, respectively. The pathology of these disorders involves the accumulation of adenine and its derivatives, which can be toxic or interfere with the normal function of different organs, such as the kidneys and the urinary tract, as well as lead to developmental delays and to severe combined immunodeficiency.

[2] Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

  • Authors: G. del Favero, A. Bonifacio, T. Rowland, Shanshan Gao, Kunhua Song et al.
  • Year: 2020
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/98c99997015d4b753548454628875ce01936b442
  • DOI: 10.3390/jcm9082457
  • PMID: 32751926
  • PMCID: 7465084
  • Citations: 17
  • Influential citations: 1
  • Summary: Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.409) > Because Danon disease is very rare, with <100 clinical reports and <200 families reported in the literature [12], there is poor availability of material for diagnosis and characterization [13]. Hence, research toward the creation of reliable models, such as animal models [14] or iPSC-CMs, enabling the study of this complex pathology even in a limited manner are essential and constantly evolving. > To determine the molecular and cellular mechanisms by which LAMP-2 deficiency results in metabolic changes, here we combined Raman spectroscopy, transcriptomics, and metabolomics approaches on cardiac tissue and cellular models derived from Danon patients. Analyses were performed on cardiac tissue biopsies from Danon patients, as well as from patient-derived hiPSC-CMs. Even with limited patient cardiac tissue, we were able to identify pathways that were similarly impacted in our cellular models, supportive of these pathways being significantly affected in Danon disease. LAMP-2 deficiency appeared to promote specific metabolic switch in cardiomyocytes, possibly adaptive, given that cardiomyocytes have a high metabolic need. The pathway analyses suggest that LAMP-2 deficiency favors glycolysis to oxidative phosphorylation (OXPHOS) and promotes alternative metabolic pathways, such as with the mobilization of tryptophan. This contributes to preserving high nicotinamide adenine dinucleotide (NAD + ) levels despite mitochondrial aging. Similarly, fibroblasts respond to LAMP-2 deficiency with a stress-associated phenotype pointing toward fibrosis progression. This was accompanied by impairment of biomechanical properties, which retraces the clinical phenotype of Danon disease.

[3] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 4
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[4] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

  • Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
  • DOI: 10.3390/metabo14100515
  • PMID: 39452896
  • PMCID: 11509386
  • Citations: 2
  • Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
  • Evidence snippets:
  • Snippet 1 (score: 0.403) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[5] Uncovering Proteomic and Biochemical Alterations in Plasma from Lesch–Nyhan Disease Patients

  • Authors: Sundas Javed, D. Braconi, Haidara Nadwa, A. Paffetti, G. Jacomelli et al.
  • Year: 2025
  • Venue: Cellular and Molecular Neurobiology
  • URL: https://www.semanticscholar.org/paper/9a62a3d01ad7438fe1e7bf6587725c4c9a576bfa
  • DOI: 10.1007/s10571-025-01644-z
  • PMID: 41398526
  • PMCID: 12804513
  • Summary: It is suggested that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.401) > Lesch–Nyhan disease (LND) is an ultra-rare X-linked inborn error of metabolism caused by complete or partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), a key enzyme in the purine salvage pathway. This defect leads to uric acid overproduction and a broad spectrum of neurological and behavioral manifestations, whose severity depends on the degree of residual enzymatic activity. Although emerging evidence implicates HPRT deficiency in widespread cellular dysfunctions, particularly within midbrain dopaminergic neurons, the molecular mechanisms underlying the neurobehavioral phenotype of HPRT deficiency remain poorly understood and are not adequately explained by purine metabolism dysfunctions alone. Although proteomics represents a powerful approach for elucidating molecular alterations underlying disease, it has so far found only limited application in LND research. To address this gap, we provide here the first proteomic study combined with clinical biochemistry data and pro-inflammatory cytokines profiling of plasma samples from 29 HPRT deficient individuals (21 with classic LND and 8 with Lesch–Nyhan variants – LNV). We suggest that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.

[6] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 38
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[7] Inborn Errors of Purine Salvage and Catabolism

  • Authors: M. Camici, M. Garcia-Gil, S. Allegrini, R. Pesi, G. Bernardini et al.
  • Year: 2023
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/d148bf0d5fd4f6a8eca5ba4751391963e98d9f69
  • DOI: 10.3390/metabo13070787
  • PMID: 37512494
  • PMCID: 10383617
  • Citations: 20
  • Summary: Diagnostic tools are suggested that may indicate to clinicians that the inborn errors of purine metabolism may not be very rare diseases after all and are offered new points of view on this topic.
  • Evidence snippets:
  • Snippet 1 (score: 0.396) > Mutations may affect different aspects of the enzyme functions, such as the kinetic parameters, or the binding of other regulating proteins or small molecules, leading to a panel of alterations in enzymatic activity and therefore to different symptoms. A complete lack of an enzyme activity may compromise vital functions resulting in life threatening diseases. Partial enzyme dysfunction may result in symptoms easily misdiagnosed as one of the many infantile syndromes characterized by neuropsychiatric, neuromotor, and neurosensorial impairments. In this regard, using metabolomic and transcriptomic approaches, dysfunctions of purine metabolism, other than the well-known ADSL deficiency, have been reported in autism spectrum disorders [304,305], such as a significant increase in ADA activity, with a reduction in UA [304], and an increase in hypoxanthine, inosine, and xanthosine [305]. Another reason for misdiagnosis is the occurrence of compensatory mechanisms, which may differ among individuals and may attenuate the effects of the purine inborn error, giving rise to various phenotypes that do not completely correlate with the genotype. > Over the years, several cell models have been developed and employed to explore the metabolic features and investigate the molecular mechanisms underpinning these rare diseases. Most studies have been initially conducted using easily available cells, such as erythrocytes and cultured fibroblasts, isolated from patients for diagnostic purposes. Other cellular models were also studied, but they quickly revealed their limitations: failing to recapitulate the different enzymatic expression or activity in different tissues or cell types, in different stages of development, or lacking several relevant pathways (e.g., protein synthesis machinery in erythrocytes). Furthermore, most of the pathologies of still unknown etiology, associated with purine inborn errors, concern the nervous system. The pathophysiology of neurological defects cannot be studied directly in the patients, because of the ethical implications of obtaining samples of brain tissue. Therefore, animal models were developed as an alternative approach, which, unfortunately, often did not completely reflect the human phenotype and failed to address many of the unresolved neurological features.

[8] Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila

  • Authors: Céline Petitgas, Laurent Seugnet, Amina Dulac, Giorgio Matassi, Ali Mteyrek et al.
  • Year: 2023
  • Venue: eLife
  • URL: https://www.semanticscholar.org/paper/834a539d0f9c7ef8b4762a6c4f31c14c3e610898
  • DOI: 10.1101/2023.06.23.546306
  • PMID: 38700995
  • PMCID: 11068357
  • Citations: 2
  • Summary: Drosophila could be used in different ways to better understand Lesch-Nyhan disease and seek a cure for this dramatic disease, as well as suggest that the fruit fly could be a suitable animal model for this cure.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > The purine salvage pathway is an essential component of cellular metabolism that allows the recovery of free purine bases derived from the diet or from the degradation of nucleic acids and nucleotides, thus avoiding the energy cost of de novo purine biosynthesis (Nyhan, 2014). Energy-intensive tissues, such as cardiac muscle and brain cells, extensively use this pathway to maintain their purine levels (Ipata, 2011;Johnson et al., 2019). The two main recycling enzymes involved in the salvage pathway in mammals are hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which converts hypoxanthine and guanine into IMP and GMP, respectively, and adenine phosphoribosyltransferase (APRT), which converts adenine into AMP. > APRT and HGPRT deficiencies induce very different disorders in humans. Loss of APRT seems to have only metabolic consequences, leading to the formation of 2,8-dihydroxyadenine crystals in kidney, which can be fatal but is readily prevented by allopurinol treatment (Bollée et al., 2012;Harambat et al., 2012). In contrast, highly inactivating mutations in HGPRT trigger Lesch-Nyhan disease (LND), a rare neurometabolic X-linked recessive disorder with dramatic consequences for child neurodevelopment (Lesch and Nyhan, 1964;Seegmiller et al., 1967). The metabolic consequence of HGPRT deficiency is an overproduction of uric acid in the blood (hyperuricemia) that can lead to gout and tophi, or nephrolithiasis (Sass et al., 1965;Kelley et al., 1967). Affected children also develop severe neurological impairments, such as dystonia, choreoathetosis, spasticity, and a dramatic compulsive self-injurious behavior (Nyhan, 1997;Jinnah et al., 2006;Torres et al., 2007a;Schretlen et al., 2005;Madeo et al., 2019).

[9] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 30
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[10] The Housekeeping Gene Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) Regulates Multiple Developmental and Metabolic Pathways of Murine Embryonic Stem Cell Neuronal Differentiation

  • Authors: T. Kang, Yongjin P. Park, J. Bader, T. Friedmann
  • Year: 2013
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/54edcbc1319338d7301bde981da800eba378740d
  • DOI: 10.1371/journal.pone.0074967
  • PMID: 24130677
  • PMCID: 3794013
  • Citations: 49
  • Influential citations: 3
  • Summary: Results of gene expression studies during neuronal differentiation of HPRT-deficient murine ESD3 embryonic stem cells are described and it is predicted that some of these systems defects play similar neuropathogenic roles in diverse neurodevelopmental and neurodegenerative diseases in common and may provide new experimental opportunities for clarifying pathogenesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > Lesch-Nyhan Disease (LND) is a monogenic neurodevelopmental disease caused by mutations in the X-linked gene encoding the purine salvage biosynthetic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) [1]. The clinical disorder is characterized by dystonia, choreoathetosis, cognitive deficits and self-injurious behavior, the hallmark feature of LND. The most prominent and well-recognized neurophysiological consequence of HPRT deficiency in the human central nervous system is dysfunction of basal ganglia dopaminergic (DA) neurons and defective development of DA signaling pathways [2][3][4][5] that in turn are thought at least partially to cause the aberrant neurological phenotype. The mechanisms connecting the defective purine pathways with neurological defects are not well understood, although most current models of LND pathogenesis assume that aberrant purine metabolism is the proximate cause of the neurological dysfunction through a direct effect of aberrant purine levels on early neural development or on neural function. > Recent studies in our laboratories have identified molecular neural dysregulatory mechanisms associated with HPRT deficiency that are likely to underlie defective neural development and aberrant function of dopaminergic and possibly other classes of neural cells. These findings point to a complex set of dysregulated functions and pathways that constitute a multi-systems set of pathogenic mechanisms responsible for this monogenic disease. Most relevant have been demonstrations of aberrant expression of key neuronal transcription factors, microRNA expression and defects in purinergic and other cellular signaling functions in a variety of mouse and human cell culture systems including human iPS cells. These defects have included aberrant canonical Wnt/bcatenin signaling and defective presenilin-1 expression [6], dysregulated expression of purinergic receptors with resulting aberrant expression of phospho-CREB and phospho-ERK signal-ing [7] and aberrant expression of microRNA expression [8].

[11] Rescuing compounds for Lesch-Nyhan disease identified using stem cell-based phenotypic screening.

  • Authors: Valentin Ruillier, Johana Tournois, Claire Boissart, Marie Lasbareilles, Gurvan Mahé et al.
  • Year: 2020
  • Venue: JCI insight
  • URL: https://www.semanticscholar.org/paper/406026bae064ce7f3e3e9df828b6bc7a2cc4890f
  • DOI: 10.1172/jci.insight.132094
  • PMID: 31990683
  • Citations: 21
  • Influential citations: 1
  • Summary: 6 pharmacological compounds are identified that corrected HGPRT deficiency-associated neuronal phenotypes by promoting metabolism compensations in an HG PRT-independent manner and can be provided to LND patients via simple food supplementation.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > In addition to these purely metabolic actions, purines activate a plethora of cell signalling pathways via membrane receptors that can act additively, synergistically, or antagonistically (2). Related to this mechanistic complexity, the precise measurement of purine intermediate concentrations requires complex techniques, such as HPLC, that are not Lesch-Nyhan disease (LND) is a rare monogenic disease caused by deficiency of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). LND is characterized by severe neuropsychiatric symptoms that currently cannot be treated. Predictive in vivo models are lacking for screening and evaluating candidate drugs because LND-associated neurological symptoms are not recapitulated in HGPRT-deficient animals. Here, we used human neural stem cells and neurons derived from induced pluripotent stem cells (iPSCs) of children affected with LND to identify neural phenotypes of interest associated with HGPRT deficiency to develop a targetagnostic-based drug screening system. We screened more than 3000 molecules and identified 6 pharmacological compounds, all possessing an adenosine moiety, that corrected HGPRT deficiencyassociated neuronal phenotypes by promoting metabolism compensations in an HGPRTindependent manner. This included S-adenosylmethionine, a compound that had already been used as a compassionate approach to ease the neuropsychiatric symptoms in LND. Interestingly, these compounds compensate abnormal metabolism in a manner complementary to the gold standard allopurinol and can be provided to patients with LND via simple food supplementation. This experimental paradigm can be easily adapted to other metabolic disorders affecting normal brain development and functioning in the absence of a relevant animal model. insight.jci.org https://doi.org/10.1172/jci.insight.132094

[12] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

  • Authors: Tian-Guang Zhang, Chaoyu Miao
  • Year: 2022
  • Venue: Acta Pharmaceutica Sinica. B
  • URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
  • DOI: 10.1016/j.apsb.2022.10.008
  • PMID: 36970208
  • PMCID: 10031255
  • Citations: 85
  • Influential citations: 1
  • Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[13] Oxidative Stress in Healthy and Pathological Red Blood Cells

  • Authors: Florencia Orrico, Sandrine Laurance, Ana C. Lopez, S. Lefevre, L. Thomson et al.
  • Year: 2023
  • Venue: Biomolecules
  • URL: https://www.semanticscholar.org/paper/5ea67232d5288f7e47b3304da16c315738a09419
  • DOI: 10.3390/biom13081262
  • PMID: 37627327
  • PMCID: 10452114
  • Citations: 124
  • Influential citations: 3
  • Summary: The most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and the role of oxidative stress in different red cell diseases are discussed, highlighting the underlying mechanisms leading to pathological RBC phenotypes are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.380) > Red cell diseases encompass a group of inherited or acquired erythrocyte disorders that affect the structure, function, or production of red blood cells (RBCs). These disorders can lead to various clinical manifestations, including anemia, hemolysis, inflammation, and impaired oxygen-carrying capacity. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms, plays a significant role in the pathophysiology of red cell diseases. In this review, we discuss the most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and finally, the role of oxidative stress in different red cell diseases, including sickle cell disease, glucose 6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency, highlighting the underlying mechanisms leading to pathological RBC phenotypes.

[14] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[15] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

  • Authors: R. Ragusa, P. Bufano, A. Tognetti, M. Laurino, Chiara Caselli
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
  • DOI: 10.3390/ijms26062571
  • PMID: 40141213
  • PMCID: 11942187
  • Citations: 6
  • Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[16] Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey

  • Authors: G. Balasubramaniam, Monica Arenas-Hernandez, E. Escuredo, L. Fairbanks, T. Marinaki et al.
  • Year: 2016
  • Venue: Clinical Kidney Journal
  • URL: https://www.semanticscholar.org/paper/f23d722e643960918e52e56484c1ecfc4544a46d
  • DOI: 10.1093/ckj/sfw093
  • PMID: 27994857
  • PMCID: 5162415
  • Citations: 4
  • Summary: An inborn error of metabolism that can cause kidney disease from crystalline nephropathy or kidney stones presents in a wide spectrum in all age groups and patients can be completely asymptomatic and kidney disease may be incorrectly attributed to other conditions.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey

[17] mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node

  • Authors: Laura Mantoan Ritter, N. M. P. Annear, E. Baple, Leila Y. Ben-Chaabane, Istvan Bodi et al.
  • Year: 2025
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/f30b2504a3b3bbb7264847da72e690aebd2919d7
  • DOI: 10.1186/s13023-025-03740-1
  • PMID: 40426219
  • PMCID: 12107773
  • Citations: 6
  • Summary: How mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients is expound.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

[18] 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: 0.375) > 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.

[19] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 10
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[20] Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

  • Authors: Carly S. Pontifex, Mashiat Zaman, R. Fanganiello, T. Shutt, G. Pfeffer
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a0717d977acc61d9c08343d1ac6aed94c33f2138
  • DOI: 10.3390/ijms25115633
  • PMID: 38891822
  • PMCID: 11172259
  • Citations: 15
  • Summary: In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mito...
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Although the major roles of VCP in protein quality control are presumed to be the major mechanisms implicated in MSP, the incredible functional diversity and pleiotropic effects of VCP also imply that other mechanisms may be relevant and require further study.VCP cooperates with the 26S proteasome, the main pathway for protein degradation, to manage the protein quality control system.In the nucleus, VCP regulates cell cycle control and the DNA damage response by coordinating proteins at DNA damage sites.In the cytosol, VCP regulates responses to cellular stress by forming and clearing stress granules, facilitating ERAD, autophagy, mitophagy and lysophagy, and VCP may also be involved in apoptosis.The complexity of VCP's diverse molecular functions is also mirrored by the variability in clinical dysfunction caused by pathogenic variants in VCP.The relationship between specific molecular functions of VCP and the spectrum of clinical presentations remains poorly understood, and, in general, genotype-phenotype correlation is still difficult to demonstrate.Certainly, VCP plays many yet-to-be-identified roles in different cellular systems.Given that the role of VCP extends to so many cellular systems, it makes it difficult to ascertain which dysfunction leads to which clinical phenotype.The majority of MSP cases are related to variants at positions 155 and 159, but the phenotypic variability is extensive, suggesting that other genetic or epigenetic factors and/or environmental factors may interact.To better narrow down a causative mechanism in a given tissue, we advise that, when possible, experiments should include one or two other MSP genes such as SQSTM1 or HNRNPA2B1, as this may help identify common mechanisms of dysfunction in MSP.Studies of large cohorts of patients who have common variants in VCP may allow for the identification of genetic modifiers or other factors that contribute to phenotypic variability.Even though pathogenic variants in VCP typically lead to multisystem disease, in general, the affected systems predictably include certain tissue types (primarily skeletal muscle, the cerebrum, motor neurons and osteoclasts).Even though VCP is ubiquitously expressed and participates in numerous crucial cellular functions, pan-systemic disease is not observed.

Notes

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