Asta Literature Retrieval: Pathophysiology and clinical mechanisms of neuroferritinopathy. Core disease mechanisms, molecular and cellular pathw...

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

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 8
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.402) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[2] Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery

• Authors: Xiao-lei Wu, Zhang-zhong Yang, Jinjun Zou, Huile Gao, Zhenhua Shao et al.
• Year: 2025
• Venue: Signal Transduction and Targeted Therapy
• URL: https://www.semanticscholar.org/paper/57c532f807605e5181ca30a675ad0d79e3625453
• DOI: 10.1038/s41392-025-02179-x
• PMID: 40328798
• PMCID: 12056177
• Citations: 33
• Influential citations: 1
• Summary: The role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases are discussed, and the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies for effective prevention and early intervention are illustrated.
• Evidence snippets:
• Snippet 1 (score: 0.395) > Neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, Huntington’s disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase–kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

[3] 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: 37
• 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: 0.390) > 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.

[4] Autosomal Dominant FTH1 Variant Causing Pontocerebellar Hypoplasia and Late-Onset Neuroferritinopathy

• Authors: J. A. Hebbink, Jikke-Mien F. Niermeijer, Elene Vroegindeweij, B. D. de Vries, S. Pegge et al.
• Year: 2026
• Venue: Neurology: Genetics
• URL: https://www.semanticscholar.org/paper/df4e201fa2a54e6942715f83f1f3505ead4ddfca
• DOI: 10.1212/NXG.0000000000200342
• PMID: 41551370
• PMCID: 12807490
• Summary: A patient with a distinct clinical and neuroradiologic phenotype and a de novo variant in the FTH1 gene, recently discovered cause of prenatal-onset cerebellar atrophy with later-onset neuroferritinopathy is reported on.
• Evidence snippets:
• Snippet 1 (score: 0.386) > We believe that a similar mechanism likely underlies the neuroferritinopathy because of FTH1 variants. This is because (1) the FTH1 variants concern truncating variants in the last exon that escape nonsense-mediated decay (as demonstrated previously), 1 (2) these truncated variants do not affect the predicted ferritin binding domain in FTH (amino acid 11 to 160; IPR033921), 8 suggesting that they are coassembled into the 24-mer ferritin complex, and (3) patient cells with these truncating FTH1 variants are sensitive to iron accumulation as a sign of decreased iron storage. 1 Since our patient and the patients reported previously, 1 presented with a congenital pontocerebellar hypoplasia and later developed basal nuclei abnormalities, both phenomena are likely caused by the FTH1 variant (Table ). Remarkably, MRI T1 hyperintensities are impressive although T2 hypointensities are subtle. SWI does not show susceptibility of these areas, which was present in 3 patients. 1 T in our patient did not show calcifications. We hypothesize that the imaging pattern might be due to a relatively low amount of iron accumulation. 9 This might also explain the phenotype variability in disease progression, with clinical regression and basal nuclei abnormalities starting at a relatively late age in our patient. Another possible explanation is additional accumulation of other substances like manganese or neuromelanin, which can be released from apoptotic pigmented neurons of the substantia nigra and can bind iron. 9,10 cause neuroferritinopathy due to heterozygous FTH1 variants appears ultrarare, and is recently discovered, there is no treatment available. There are no known drugs to manipulate or enhance the cellular disposal mechanism and reduce the ferritin accumulation. 11 Chelation therapy is currently being studied in different types of neuroferritinopathy, with the first results showing that early treatment initiation results in a better clinical response. 12 Because our patient is in a late disease stage and experiencing a high level of disability, we do not expect a significant response of chelation therapy. Genetic therapy is increasingly being considered as a promising therapy.

[5] Renal ciliopathies: promising drug targets and prospects for clinical trials

• Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
• Year: 2023
• Venue: Expert Opinion on Therapeutic Targets
• URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
• DOI: 10.1080/14728222.2023.2218616
• PMID: 37243567
• Citations: 10
• Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
• Evidence snippets:
• Snippet 1 (score: 0.385) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

[6] Psychobiotics at the Frontiers of Neurodegenerative and Neuropsychiatric Research

• Authors: Guillermo Roberto Jiménez-Pareyón, J. Cristóbal-Luna, Y. García-Martínez, Cynthia Garfias-Noguez, Morayma Ramírez-Damián et al.
• Year: 2025
• Venue: Microorganisms
• URL: https://www.semanticscholar.org/paper/6c92b8101905064ff4e4e8585f4fa86ebfac0826
• DOI: 10.3390/microorganisms13122718
• PMID: 41471921
• PMCID: 12735313
• Summary: A review of current evidence on the GBA’s involvement in conditions such as Alzheimer’s disease, Parkinson’s disease, depression, and anxiety examines how psychobiotics may modulate neuroinflammation, oxidative stress, and neurotransmitter signaling, thereby contributing to cognitive and emotional regulation.
• Evidence snippets:
• Snippet 1 (score: 0.378) > Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive deterioration of the central or peripheral nervous system. These diseases cause morphological changes in the brain, leading to significant cognitive or motor impairments, debilitating symptoms, and a reduced quality of life [16]. NDs involve complex cellular responses triggered by the accumulation of pathologically altered brain substances, ultimately resulting in irreversible loss of neuronal populations [17]. > The pathophysiology of NDs is multifactorial and intricate, involving cellular, molecular, and genetic mechanisms. These include protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, cytoskeletal abnormalities, disrupted synaptic networks, neuronal death, aberrant cell proliferation, neuroinflammation, demyelination, altered axonal transport, dysregulated energy metabolism, and abnormal modifications of DNA or RNA [16,[18][19][20][21][22]. > NDs can be classified according to several criteria, such as their etiology, the molecular mechanisms involved, and the anatomical regions affected [23]. Although multiple classification systems exist, these disorders often share overlapping cellular and molecular mechanisms [24], which complicates efforts to categorize them into a single scheme. From a mechanistic perspective, NDs commonly exhibit recurring pathological events such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and the accumulation of misfolded proteins [16]. Recent classification systems increasingly emphasize the type of protein aggregates for diagnostic accuracy [25]. Clinically, NDs can also be classified clinically based on predominant symptoms, such as movement disorders in PD and Huntington's disease, cognitive deficits in AD, or a combination of both [12,26,27]. This approach allows for a better understanding of their heterogeneity and facilitates the development of more specific therapeutic strategies. Among the spectrum of neurodegenerative conditions, AD and PD are the most prevalent and extensively studied (Figure 1).

[7] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

• Authors: O. Tsukamoto
• Year: 2019
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
• DOI: 10.3390/ijms21010226
• PMID: 31905684
• PMCID: 6982115
• Citations: 16
• Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[8] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

• Authors: Christine Péladeau, J. Sandhu
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
• DOI: 10.3390/ijms22116068
• PMID: 34199845
• PMCID: 8200055
• Citations: 18
• Influential citations: 1
• Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[9] 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: 0.375) > 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.

[10] 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: 3
• 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: 0.373) > 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.

[11] Organoids in gastrointestinal diseases: from bench to clinic

• Authors: Qinying Wang, Fanying Guo, Qinyuan Zhang, Tingting Hu, Yutao Jin et al.
• Year: 2024
• Venue: MedComm
• URL: https://www.semanticscholar.org/paper/9b8880d8b9d45670da950197d7e353794f51d09e
• DOI: 10.1002/mco2.574
• PMID: 38948115
• PMCID: 11214594
• Citations: 12
• Summary: A comprehensive and systematical depiction of organoids models is drawn, providing a novel insight into the utilization of organoids models from bench to clinic and clinical adhibition.
• Evidence snippets:
• Snippet 1 (score: 0.373) > Organoids models offer a robust platform for investigating the potential mechanisms of GI diseases and evaluating potential therapeutic interventions.By culturing organoids derived from patients' tissues or stem cells, researchers can delve into disease-specific cellular and molecular pathways, encompassing aberrant cell signaling, perturbed immune responses, and dysfunctional metabolic processes.These disease-specific phenotypes enable the study of disease progression, screening of prospective therapeutics, as well as identification of novel drug targets and mechanisms of action for GI diseases in a clinically relevant context.

[12] 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: 14
• 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.

[13] Neuroferritinopathy: Pathophysiology, Presentation, Differential Diagnoses and Management

• Authors: Niraj Kumar, P. Rizek, M. Jog
• Year: 2016
• Venue: Tremor and Other Hyperkinetic Movements
• URL: https://www.semanticscholar.org/paper/127b16c0ff2c22a6cad28a7fb9eb091b94ac8d25
• DOI: 10.7916/D8KK9BHF
• PMID: 27022507
• PMCID: 4795517
• Citations: 41
• Summary: NF must be considered in patients presenting clinically as a progressive movement disorder with variable phenotype and imaging evidence of iron deposition within the brain, decreased serum ferritin, and negative genetic testing for other more common movement disorders such as Huntington’s disease.
• Evidence snippets:
• Snippet 1 (score: 0.369) > Neuroferritinopathy: Pathophysiology, Presentation, Differential Diagnoses and Management

[14] Nuclear damages and oxidative stress: new perspectives for laminopathies

• Authors: G. Lattanzi, S. Marmiroli, Andrea Facchini, N. Maraldi
• Year: 2012
• Venue: European Journal of Histochemistry : EJH
• URL: https://www.semanticscholar.org/paper/8611d2c59658a5c3139c153051a0a4d8881c55ea
• DOI: 10.4081/ejh.2012.e45
• PMID: 23361241
• PMCID: 3567764
• Citations: 49
• Influential citations: 3
• Summary: The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathies patients.
• Evidence snippets:
• Snippet 1 (score: 0.369) > Mutations in genes encoding nuclear envelope proteins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, referred to as laminopathies. The astonishing variety of diseased phenotypes suggests that different mechanisms could be involved in the pathogenesis of laminopathies. In this review we will focus mainly on two of these pathogenic mechanisms: the nuclear damages affecting the chromatin organization, and the oxidative stress causing un-repairable DNA damages. Alteration in the nuclear profile and in chromatin organization, which are particularly impressive in systemic laminopathies whose cells undergo premature senescence, are mainly due to accumulation of unprocessed prelamin A. The toxic effect of these molecular species, which interfere with chromatin-associated proteins, transcription factors, and signaling pathways, could be reduced by drugs which reduce their farnesylation and/or stability. In particular, inhibitors of farnesyl transferase (FTIs), have been proved to be active in rescuing the altered cellular phenotype, and statins, also in association with other drugs, have been included into pilot clinical trials. The identification of a mechanism that accounts for accumulation of unrepairable DNA damage due to reactive oxygen species (ROS) generation in laminopathic cells, similar to that found in other muscular dystrophies (MDs) caused by altered expression of extracellular matrix (ECM) components, suggests that anti-oxidant therapeutic strategies might prove beneficial to laminopathic patients.

[15] Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?

• Authors: Francesco Agostini, Bibiana Sgalletta, M. Bisaglia
• Year: 2024
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/631a7816a83f4dc7c213df8145bb6d8c78f2fd66
• DOI: 10.3390/cells13161376
• PMID: 39195264
• PMCID: 11352641
• Citations: 7
• Summary: The picture that emerges is that, while iron overload can contribute to the pathogenesis of NBIA, it does not seem to be the causal factor in most forms of the pathology.
• Evidence snippets:
• Snippet 1 (score: 0.366) > NBIA encompasses a class of heterogeneous neurodegenerative, still incurable disorders that have as a common denominator the accumulation of iron in the brain. At present, 10 genes have been associated with this pathology (Figure 3). While the analysis of the different genetic forms of NBIA allowed the definition of cellular pathways potentially involved in the pathogenesis, several unanswered questions need to be considered for a better understanding of the disease and the definition of therapeutic strategies. > A crucial aspect that needs to be tackled is the precise role of iron in NBIA pathology. While its involvement in NBIA-related pathological processes is obvious, it has not been established yet whether iron accumulation is the primary cause or a consequence of the cellular processes mainly affected by NBIA. The analysis of the cellular mechanisms associated with the different NBIA subtypes described in this review leads us to suggest that iron deposition represents one of the characteristic features rather than a common cause of the pathological phenotype. In fact, besides neuroferritinopathy and aceruloplasminemia, in which iron dyshomeostasis appears as the triggering factor of the pathology, the other NBIA subtypes are more likely elicited by other factors. Alterations in lipid metabolism and/or mitochondrial and lysosomal defects could represent causal events in the disease onset and progression, leading to iron overload as a consequential effect. However, since all these processes mutually influence each other, further investigation is required to definitely resolve this issue.

[16] Heat Shock Proteins in Oxidative Stress and Ischemia/Reperfusion Injury and Benefits from Physical Exercises: A Review to the Current Knowledge

• Authors: Jakub Szyller, I. Bil-Lula
• Year: 2021
• Venue: Oxidative Medicine and Cellular Longevity
• URL: https://www.semanticscholar.org/paper/4ec4bee9f1b89cdf5a3c513d847990f3cfc18bb8
• DOI: 10.1155/2021/6678457
• PMID: 33603951
• PMCID: 7868165
• Citations: 112
• Influential citations: 2
• Summary: The latest research focuses on determining the role of H SPs in OS, their antioxidant activity, and the possibility of using HSPs in the treatment of I/R consequences, where reactive oxygen species play a major role.
• Evidence snippets:
• Snippet 1 (score: 0.366) > Heat shock proteins play a cytoprotective role under pathological conditions such as cardiovascular diseases. The knowledge about cellular and molecular mechanisms underlying ROS-mediated modulation of HSP expression can help to better understand the pathophysiology of OS, which is associated with the development of many diseases (cardiovascular, neurodegenerative, etc.). I/R injury is considered a major contributor to tissue damage in multiple clinical situations such as myocardial infarction, stroke, and organ transplantation. Oxidative damage is a key factor in the initiation of I/R. HSP expression is highly sensitive to I/R injury. > Understanding the exact mechanisms of HSP and the structure of the protein interaction network can help to better understand the pathophysiology and treatment of many diseases, as well as to develop new drugs. There is a need to understand the relationship between cell pathways-signaling, metabolism, etc. The relationships between HSP and OS discussed in this work seem to be very complicated and not yet fully understood. Data showed that modulation of HSP expression in reperfusion injuries may result in better treatment of myocardial infarction. This can also help to prepare organs for the transplantation.

[17] Abnormal iron metabolism in fibroblasts from a patient with the neurodegenerative disease hereditary ferritinopathy

• Authors: A. Barbeito, T. Levade, M. Delisle, B. Ghetti, R. Vidal
• Year: 2010
• Venue: Molecular Neurodegeneration
• URL: https://www.semanticscholar.org/paper/e8da91825af53326adb6a227293d8d0fae1ca0d2
• DOI: 10.1186/1750-1326-5-50
• PMID: 21067605
• PMCID: 2993710
• Citations: 32
• Summary: HF fibroblasts are a unique cellular model in which to study the role of abnormal iron metabolism in the pathogenesis of HF without artifacts derived from over-expression or lack of endogenous translational regulatory elements.
• Evidence snippets:
• Snippet 1 (score: 0.366) > The neurodegenerative disease neuroferritinopathy or HF is an autosomal dominant, adult onset disease caused by mutations in the FTL gene that lead to the production of FTL polypeptides with abnormal C-termini [3][4][5][6][7][8][9]24]. The clinical presentation of HF varies both within and between families. Patients may present with tremor, cerebellar signs, parkinsonism, psychiatric problems, abnormal involuntary movements (dystonia, chorea), pyramidal syndrome, pseudo-bulbar symptoms, and cognitive deficit [3][4][5][6][7][8][9][10]. Magnetic resonance imaging shows abnormal signals in the globus pallidus and putamen, and cavitation in the putamen [5,10]. Mild cerebral and cerebellar atrophy may be observed. Serum ferritin levels may be within normal range or even decreased in some patients [4]. Neuropathologic studies show cavitation in the putamen [4][5][6]. The cerebrum and cerebellum are atrophic. Ferritin IBs are found in nuclei and cytoplasm of glial cells and neurons in the CNS as well as in cells of other organ systems and are labeled by antibodies against light and heavy chains of ferritin and antibodies specific for the mutant FTL polypeptide [5]. Abnormal iron accumulation (both as ferrous and ferric iron) associated with ferritin IBs has been described [4][5][6] as well as evidence of oxidative damage in patients [6] and in animal models [17,25]. Thus, disrupted iron homeostasis and ironmediated oxidative stress may have a major role in the pathogenesis of HF [3,24]. > We investigated cellular iron metabolism in primary cell cultures of skin fibroblasts from an individual with the c.497_498dupTC mutation to determine whether fibroblasts would be an accessible in vitro system in which to directly examine disease-relevant pathologic mechanisms in HF.

[18] Omics Data and Their Integrative Analysis to Support Stratified Medicine in Neurodegenerative Diseases

• Authors: Valentina La Cognata, Giovanna Morello, S. Cavallaro
• Year: 2021
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/fd3586b07f23e89cece5c7ea2abc6fddd871568e
• DOI: 10.3390/ijms22094820
• PMID: 34062930
• PMCID: 8125201
• Citations: 35
• Summary: How omics technologies and their integration have provided new insights into the molecular heterogeneity underlying the most prevalent NDs, aiding to define early diagnosis and progression markers as well as therapeutic targets that can translate into stratified treatment approaches are discussed, bringing us closer to the goal of personalized medicine in neurology.
• Evidence snippets:
• Snippet 1 (score: 0.363) > Neurodegenerative diseases (NDs) are debilitating and largely untreatable conditions characterized by a decline of nervous system functions due to a progressive neuronal loss in the brain and spinal cord. The classification of NDs is still usually based on the clinical presentation (i.e., cognitive decline, speech difficulties and motor impairment), anatomical regions and cell types affected [1,2]. As the exact molecular mechanisms of the disease pathogenesis and progression remain unclear, the clinical management of NDs is limited to simply mitigating neurodegeneration and relieving symptoms rather than reversing the damage done [1,3,4]. > NDs can be either monogenic, like Huntington disease, or complex, highly heterogeneous-including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS)-and characterized by variable molecular phenotypes, progression courses or patterns of neuro-biochemical markers of brain damage, making patient counseling, disease management and pharmaceutical care particularly difficult [3]. The underlying mechanisms of these complex NDs are polyfactorial and depend on the combination of genetic, biological and environmental factors. The presence of abnormal protein conformations, excessive immune response and inflammation, impaired nucleocytoplasmic transport, mitochondrial dysfunction, neuronal dysfunction and autophagy are common features of neurodegeneration [5,6]. However, despite considerable efforts, the molecular mechanisms involved in the complex phenotype of NDs are still largely unknown, and current treatments cannot prevent the development of the disease. The failure of the majority of neurological clinical trials, especially during Phase 3, can be attributed to a lack of efficacy, probably due to the incorrect selection of the target population [7,8]. A full readout of ND conditions to support stratified medicine. From the genome onwards, information gathered from all omics molecular layers of NDs conditions will aid researchers and clinicians to better characterize the disease's molecular heterogeneity, stratify patients by novel biomarkers and improve therapeutic outcomes.

[19] Molecular insights into the premature aging disease progeria

• Authors: Sandra Vidak, R. Foisner
• Year: 2016
• Venue: Histochemistry and Cell Biology
• URL: https://www.semanticscholar.org/paper/60fb3b46bb7e42d5d08cc3b7cbc783b118300c31
• DOI: 10.1007/s00418-016-1411-1
• PMID: 26847180
• PMCID: 4796323
• Citations: 105
• Influential citations: 3
• Summary: Changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.361) > The number of molecular biological studies aiming at the identification of lamin-mediated molecular disease mechanisms involved in HGPS increased tremendously following the surprising discovery that LMNA is causally linked to the premature aging disease HGPS in 2003. Despite numerous cellular pathways that were identified to be affected by the expression of the mutant lamin A protein (Fig. 2), the mechanistic details behind these effects are still unclear in most cases. Knowledge based on what was already known on lamin biology before the protein was linked to HGPS and findings on novel roles of lamins in diverse pathways in recent years allowed the launch of translational studies and the efficient search for drug targets and therapeutic approaches within a short time period. The results of the first clinical trials taught us that some improvements of the disease phenotypes can be achieved by FTI treatment, but they also made clear that we need a much better understanding of the underlying disease mechanisms to be able to tackle specific aspects of the disease in a more focused approach. It will also be important to elucidate which of the numerous pathways found to be impaired in HGPS are most relevant for and causally involved in the pathologies, and which ones are just bystanders.

[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: 0.357) > 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.