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Krabbe Disease

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Krabbe Disease. Core disease mechanisms, molecular and cellular pathways,...

2026-03-30
Asta MONDO:0009499 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Krabbe Disease. Core disease mechanisms, molecular and cellular pathways,...

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

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Fingolimod Rescues Demyelination in a Mouse Model of Krabbe's Disease

  • Authors: Sibylle Béchet, S. O'Sullivan, J. Yssel, S. Fagan, K. Dev
  • Year: 2020
  • Venue: The Journal of Neuroscience
  • URL: https://www.semanticscholar.org/paper/175e515f4776469b92625a06c1089c12fe11644d
  • DOI: 10.1523/JNEUROSCI.2346-19.2020
  • PMID: 32127495
  • PMCID: 7141882
  • Citations: 23
  • Influential citations: 1
  • Summary: The administration of the therapy known as fingolimod in a mouse model of Krabbe's disease (namely, the twitcher mouse model) significantly rescues myelin levels and regulates the reactivity of glial cells, astrocytes and microglia, in this mouse model.
  • Evidence snippets:
  • Snippet 1 (score: 0.500) > Krabbe's disease (KD; globoid cell leukodystrophy) is a devastating illness that is invariably fatal within the first 2 years of life (Graziano and Cardile, 2015). This disease has orphan status affecting ϳ1:100,000 births, although the incidence varies in different populations (Barczykowski et al., 2012). Krabbe's disease is an inherited lipid storage disorder resulting from oligodendrocyte cell death and subsequent loss of myelin. The disease is caused by mutations in the galc gene encoding for galactosylceramidase (galc; Suzuki and Suzuki, 1970). Mutations in galc result in enzymatic dysfunction and a buildup of its two metabolites galactosylceramide and the toxic galactolipid galactosylsphingosine (psychosine; Suzuki, 1998). Aggregations of the latter are particularly apparent in the white matter (WM) of the brain and in sciatic nerves, where it has been shown to inhibit some critical cell processes resulting in oligodendrocyte and Schwann cell apoptosis (Giri et al., 2008;Misslin et al., 2017). Pathological features of Krabbe's disease therefore include profound demyelination and almost complete loss of oligodendrocytes in the white matter, accompanied by inflammatory mechanisms including reactive astrocytosis and infiltration of numerous multinucleated phagocytes termed "globoid cells" (Suzuki, 2003). > The clinical phenotype of Krabbe's disease is classified based on the age of disease onset, with the majority of cases affecting infants (Wenger et al., 2016). Infantile Krabbe's disease typically develops within the first 6 months postnatally with progressive rapid neurologic deterioration. Hallmark symptoms of the classic infantile forms include irritability, hypertonic spasticity, and psy-chomotor stagnation, followed by rapid developmental decline, seizures, and optic atrophy (Graziano and Cardile, 2015). Clinical manifestations thus suggest involvement of both the first and second motor neurons, indicative of a systemic disorder affecting the central as well as the peripheral nervous systems.

[2] Human iPSC-derived astrocytes generated from donors with globoid cell leukodystrophy display phenotypes associated with disease

  • Authors: Richard Lieberman, Leslie K. Cortes, Grace Gao, Hyejung Park, Bing Wang et al.
  • Year: 2022
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/b5bb977bb3c00e7ca3e3e60ed073d99324ef20a1
  • DOI: 10.1371/journal.pone.0271360
  • PMID: 35921286
  • PMCID: 9348679
  • Citations: 7
  • Summary: It is suggested that astrocytes may contribute to the progression of Krabbe disease and warrant further exploration into their role as therapeutic targets.
  • Evidence snippets:
  • Snippet 1 (score: 0.464) > Second, the enzyme that synthesizes the neuroinflammatory mediator prostaglandin D2 (HPDGS) is increased in twitcher microglia, and its receptor, prostaglandin DP1, is upregulated in activated twitcher astrocytes. HPDGS inhibition or genetic ablation of the DP1 receptor ameliorated disease phenotypes including astrogliosis, demyelination, and oligodendrocyte apoptosis in the rodent model [37]. Overall, the contribution of astrocytes to the pathology of leukodystrophies is of expanding interest [38], sparked by findings that mutations specifically in astrocyte-expressing glial-fibrillary acidic protein (GFAP) gene cause demyelinating Alexander disease [39], defective support and differentiation of astrocytes results in vanishing white matter disease [40][41][42], and astrocyte dysfunction precedes demyelination observed in X-linked adrenoleukodystrophy [43], among many others [44,45]. Therefore, examination of how Krabbe astrocytes impact neurons and microglia warrant further study, particularly in the setting of human Krabbe patient-derived cells. > iPSCs generated from human fibroblasts [46] offer the ability to differentiate patientderived, disease-relevant cell types. While the murine model of Krabbe disease recapitulates aspects of the human condition [35], and iPSCs have been generated from these mice for differentiation into disease-specific cell types in vitro [47], generation of human-derived cell types relevant to Krabbe disease may provide valuable insight into novel mechanisms related to disease progression. For example, a recent study demonstrated GALC-dependent psychosine accumulation and defective differentiation of human iPSCs into a mixed population of neurons, astrocytes, and oligodendrocyte precursors [48]. Additional studies are needed to elucidate cellular mechanisms implicated in neuropathology, including experiments designed to examine effects of GALC mutations of specific cell types, including astrocytes.

[3] Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death Published, JLR Papers in Press, April 27, 2006.

  • Authors: Shailendra Giri, Mushfiquddin Khan, R. Rattan, Inderjit Singh, Avtar K. Singh
  • Year: 2006
  • Venue: Journal of Lipid Research
  • URL: https://www.semanticscholar.org/paper/9ac70ad900fac96c3f0af2a7c1771f88bd1f9b81
  • DOI: 10.1194/jlr.M600084-JLR200
  • PMID: 16645197
  • Citations: 117
  • Influential citations: 9
  • Summary: It is documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA1 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.451) > of patients with Krabbe disease, leading to the conclusion that progressive accumulation of psychosine is the critical biochemical pathogenetic mechanism of cell death in the Krabbe brain (5,6,10). We have recently reported that psychosine mediates oligodendrocyte cell death via upregulation of reactive oxygen species (ROS)-JNK-AP-1, a pro-apoptotic pathway, and downregulation of the NF-nB pathway, an antiapoptotic pathway (4). However, the mechanism of action of psychosine in the pathophysiology of Krabbe disease is not completely understood. > The observed expression of inflammatory mediators such as TNFa, IL-6, and iNOS in the central nervous systems (CNSs) of Krabbe disease patients and in twitcher mice indicates that the inflammatory response may play a role in the pathobiology of Krabbe disease (7,10). Inflammatory cytokines are known to induce the phospholipase A2 (PLA2) enzyme system. PLA2s hydrolyze phospholipids at the sn-2 position and generate lysolipids and free fatty acids, including arachidonic acid (AA). These mediators are critically involved in the regulation of several physiological events, including cell death (11,12). The PLA2s have been divided into three major groups based on size, ability to be secreted, and calcium dependency (11). The three groups consist of low-molecular-mass sPLA 2 , (13.5-16.8 kDa), calcium-independent phospholipase A 2 (iPLA 2 , 80 kDa), and high-molecular-mass cytosolic phospholipase A 2 (cPLA 2 , 85 kDa) (11). The cPLA 2 , when activated by phosphorylation via an increase in the cytosolic concentration of calcium, translocates from the cytosol to either the nuclear membrane, endoplasmatic reticulum, Golgi, or plasma membrane, depending on cell type and stimulus (12)(13)(14)(15),

[4] Revisiting magnetic resonance imaging pattern of Krabbe disease – Lessons from an Indian cohort

  • Authors: K. Muthusamy, S. Sudhakar, Maya Thomas, S. Yoganathan, Christhunesa Christudass et al.
  • Year: 2019
  • Venue: Journal of Clinical Imaging Science
  • URL: https://www.semanticscholar.org/paper/265c3bcb602164ee564977c11d0e7323fc5e8168
  • DOI: 10.25259/JCIS-18-2019
  • PMID: 31448176
  • PMCID: 6702867
  • Citations: 28
  • Summary: Kabbe disease shows distinct imaging features which correspond to different clinical age-based subtypes, which are reemphasized, highlights a novel imaging appearance in juvenile Krabbe, and also alludes to the rare variant of saposin deficiency.
  • Evidence snippets:
  • Snippet 1 (score: 0.429) > Context: Krabbe disease shows considerable heterogeneity in clinical features and disease progression. Imaging phenotypes are equally heterogeneous but show distinct age-based patterns. It is important for radiologists to be familiar with the imaging spectrum to substantially contribute toward early diagnosis, prognostication, and therapeutic decisions. Aims: The study aims to describe different magnetic resonance imaging (MRI) patterns observed in a cohort of children with Krabbe disease and to assess correlation with age-based clinical phenotypes. Materials and Methods: This is a retrospective descriptive study done at the Departments of Radiodiagnosis and Neurological Sciences of our institution, a tertiary care hospital in Southern India. Imaging features of children diagnosed with Krabbe disease over a 10-year period (2009–2018) were collected and analyzed. Results: A total of 38 MRI brain studies from 27 patients were analyzed. Four distinct MRI patterns were recognizable among the different clinical subtypes. All patients from the early and late infantile group showed deep cerebral and cerebellar white matter and dentate hilum involvement. Optic nerve thickening was, however, more common in the former group. Adult-onset subtype showed isolated involvement of corticospinal tract, posterior periventricular white matter, and callosal splenium with the absence of other supra- and infra-tentorial findings. Juvenile subgroup showed heterogeneous mixed pattern with 78% showing adult subtype pattern and 22% showing patchy involvement of deep cerebral white matter with dentate hilum signal changes. Conclusion: Krabbe disease shows distinct imaging features which correspond to different clinical age-based subtypes. This article reemphasizes these distinct imaging phenotypes, highlights a novel imaging appearance in juvenile Krabbe, and also alludes to the rare variant of saposin deficiency. Awareness of these patterns is essential in suggesting the appropriate diagnosis and guiding conclusive diagnostic workup. Large multicenter longitudinal studies are needed to further define the role of imaging in predicting the clinical course and thus to guide therapeutic options.

[5] 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: 0.427) > 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.

[6] 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: 0.412) > 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.

[7] 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: 2
  • 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: 0.400) > 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.

[8] 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: 81
  • 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: 0.399) > 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 .

[9] Glial cells in the driver seat of leukodystrophy pathogenesis.

  • Authors: L. M. Garcia, J. Hacker, Sunetra Sase, L. Adang, Akshata A Almad
  • Year: 2020
  • Venue: Neurobiology of disease
  • URL: https://www.semanticscholar.org/paper/8ce00b0863364b1b2dc5c3c676ba70b914b74660
  • DOI: 10.1016/j.nbd.2020.105087
  • PMID: 32977022
  • Citations: 22
  • Influential citations: 1
  • Summary: This review takes a closer look at multiple leukodystrophies, classified based on the primary glial cell type that is affected, and discusses how astrocytes and microglia are affected and impinge on oligodendrocyte, myelin and axonal pathology.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > to demyelination; Treatments for Krabbe include AAV-mediated gene therapy, BMT, ERT, and HSCT to upregulate the expression of GALC enzyme. Psychosine turns on cell death pathways in OPCs and OLs and also activates microglia. The activated J o u r n a l P r e -p r o o f microglia display characteristic morphology of globoid, multinucleated phagocytes and secrete cytokines, ultimately leading to OL toxicity and demyelination; Treatment for Krabbe Disease include AAV-mediated gene therapy, BMT, ERT, and HSCT to upregulate the expression of GALC enzyme; 2. ALSP: Mutation in CSF1R affects microglial proliferation and reduces microglia number affecting OL survival and causing demyelination due to unknown mechanisms; Treatment for ALSP involves elimination or repolarization of tumor-associated macrophages (TAM) with immunomodulatory drugs that inhibit CSF1R; 3. PLOSL: Mutations in the TREM2 and DAP12 genes result in dysfunction of both osteoclasts and microglia. This disrupts the ability of activated microglia turned phagocytes to recognize cellular debris, leading to decreased clearance of myelin and axonal with ongoing myelin loss; Treatments for PLOSL are not yet known; 4. X-ALD: Mutation in ABCD1 gene fails to transport VCLFA in peroxisomes. This build-up of VCLFA leads to oxidative stress and microglia death, which eventually causes OL death and myelin loss; Treatments for X-ALD mostly includes transplantation strategies such as HSCT, HCT, and BMT to prevent progression of the disease phenotype; 5. MLD: > Mutation in the ARSA gene results in accumulation of sulfatides in multiple cell types, including OLs, astrocytes, neurons, Schwann cells, and phagocytes. This sulfatide accumulation activates microglia along with OL toxicity and ultimately leads to demyelination; Treatments for MLD seek to stabilize disease progression through HSCT, UCBT, ERT, BMT, and gene therapy.

[10] 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: 9
  • 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: 0.396) > 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.

[11] Neuroimmune mechanisms in Krabbe's disease

  • Authors: Gregory B Potter, Magdalena A. Petryniak
  • Year: 2016
  • Venue: Journal of Neuroscience Research
  • URL: https://www.semanticscholar.org/paper/201f7962337a320d01bf40c225f3321e3846fafd
  • DOI: 10.1002/jnr.23804
  • PMID: 27638616
  • PMCID: 5129482
  • Citations: 53
  • Influential citations: 4
  • Summary: Mechanistic insight into the inflammatory pathways participating in myelin and axon loss or preservation may lead to novel therapeutic approaches for Krabbe's disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.396) > Leukodystrophies are the most common cause of pediatric neurodegeneration, associated with profound childhood morbidity and mortality and resulting in significant emotional and financial burden on families and society (Kohlschutter and Eichler, 2011). Although white matter degeneration is a common feature of these disorders, the activation of the CNS's innate immune response is also observed in most leukodystrophies and coincides with white matter pathology, disease progression, and morbidity (Vitner et al., 2010). Despite this, there is a major gap in our knowledge of the contribution of the immune system to disease phenotype. Krabbe's disease (KD), a leukodystrophy caused by an enzymatic defect in lysosomal galactocerebrosidase (GALC), presents in the most severe infantile form by 6 months of age, followed by death at 2 years of age (Wenger, 1997). This Review refers to neuroinflammation as inflammation characterized by reactivation of resident CNS innate immune cells (microglia) and astrogliosis, which has been previously used to describe aspects of KD pathophysiology (Snook et al., 2014;Hawkins-Salsbury et al., 2015;Lin et al., 2015). It is important to note that there is no clear consensus on the definition or application of the term neuroinflammation with regard to neurodegenerative or lysosomal storage disorders. Some researchers draw a distinction between immune-driven pathology in the brain (i.e., as seen in multiple sclerosis) and innate immune cell activation in the brain (Graeber, 2014), whereas others suggest dividing neuroinflammation between innate immunedriven and adaptive immune-driven neuroinflammation (Heppner et al., 2015). Nevertheless, it is clear that inflammation within the nervous system is a defining characteristic of KD. One of the earliest clinical SIGNIFICANCE Although innate immune activation is a central component of Krabbe's disease that precedes and accelerates with disease progression, the mechanisms by which the immune system contributes to neurodegeneration are still unclear.

[12] “Betwixt Mine Eye and Heart a League Is Took”: The Progress of Induced Pluripotent Stem-Cell-Based Models of Dystrophin-Associated Cardiomyopathy

  • Authors: D. Rovina, Elisa Castiglioni, Francesco Niro, Sara Mallia, G. Pompilio et al.
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/9303acc2a5c14adba1c342a87f27f2ae2a57195d
  • DOI: 10.3390/ijms21196997
  • PMID: 32977524
  • PMCID: 7582534
  • Citations: 3
  • Summary: Cardiovascular cells derived from muscular dystrophy patients’ induced pluripotent stem cells are well suited to mimic dystrophin-associated cardiomyopathy and hold great promise for the development of future fully effective therapies.
  • Evidence snippets:
  • Snippet 1 (score: 0.393) > Since inception, iPSC technology has shown enormous potential to model disease, solving many challenges associated with traditional approaches such as animal and primary cell/tissue models. On the basis of their characteristics, patient-specific iPSCs can provide disease-related cells which may have been previously inaccessible, e.g., neurons and cardiomyocytes. Taking advantage of these intrinsic properties, iPSCs carrying patient-specific mutations can be used to model the molecular mechanisms underlying the disease pathophysiology and screen responses to various types of therapeutics. The phenotype ranges that can be investigated by iPSC models involve a broad range of molecular, metabolic, electrophysiological, and cellular analytic techniques. iPSC disease models have been widely applied to study monogenic disorders that are caused by a single gene mutation [130] and sporadic complex disorders involving multiple or unknown genes [131]. The use of iPSC-based models for the latter disease type is more problematic with respect to monogenic diseases, since the phenotype is often the result of multiple small-effect genetic variants in combination with environmental factors. However, this approach was used to model many different complex diseases including Alzheimer's disease, Parkinson's disease, schizophrenia, and cardiac arrhythmias [132][133][134][135]. Without knowing the detailed underlying genetics, differentiated patient-specific iPSCs could provide disease-relevant cells that carry all the genetic elements implicated in the development of the disease and can be useful to analyze the common mechanisms of disease development. Indeed, patient-specific iPSCs obtained from multiple affected individuals that show similar phenotypes could be comparatively investigated in order to find common altered mechanistic pathways or functional activities. > One of the major issues concerning disease modeling using iPSCs is the relative immaturity of the cells differentiated from iPSCs. On the basis of this observation, iPSC-based models are considered more suitable for disorders with an early onset rather than late onset, for which cellular aging could play a role in the disease phenotype. However, despite their fetal phenotype, iPSC-derived cells have highlighted different phenotypes, suggesting that the pathology starts before the appearance of clinical symptoms, potentially allowing the discovery of novel mechanisms involved in the development of pathology [52,136]. > Recently, in

[13] New Insights into Mitochondria in Health and Diseases

  • Authors: Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang et al.
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/23002a4ffabfd043f52c664f4d5acab85b8dcac0
  • DOI: 10.3390/ijms25189975
  • PMID: 39337461
  • PMCID: 11432609
  • Citations: 36
  • Summary: This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities and provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > Mitochondria are essential organelles within cells, playing critical roles not only in energy metabolism but also in various cellular activities, such as cell differentiation, signal transduction, and apoptosis. Mitochondrial dysfunction is implicated in a range of diseases, including but not limited to diabetes and its complications, neurodegenerative disorders, myocardial ischemia-reperfusion injury, and heart failure. Therefore, investigating the structure and function of mitochondria as well as the mechanisms underlying mitochondrial dysfunction in disease contexts holds significant scientific and clinical importance. > Basic scientific research: Diseases manifest systemically and exhibit complexity; thus, it is imperative to understand mitochondrial structure at the molecular level along with known pathways while characterizing novel pathways that influence mitochondrial behavior and functionality. For instance, mapping genetic interactions among genes encoding mitochondrial proteins can elucidate interrelations between different aspects of mitochondrial function. The first focused map of mitochondria has been constructed in yeast models, revealing dense and significant connections among localization pathways distributed across various mitochondrial compartments [126]. > Disease diagnosis: A comprehensive understanding of the mechanisms governing mitochondrial dysfunction can facilitate the development of innovative diagnostic tools. By monitoring specific indicators related to mitochondrial function, earlier diagnosis of diseases associated with mitochondrial impairment becomes feasible. Employing nextgeneration sequencing technologies for analyzing the mitochondrial proteome aids in identifying novel proteins and pathways linked to mitochondria while enabling streamlined diagnostics alongside genetic counseling opportunities for patients with mitochondrial diseases [127]. > Drug development: Advancements in our comprehension of how mitochondria contribute to disease processes may promote targeted therapeutic strategies. For example, metformin-a widely used antidiabetic agent-has recently been repurposed as an anticancer drug; its combination with standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improves progression-free survival rates and overall survival outcomes for patients with advanced lung adenocarcinoma [125]. > Personalized medicine: Given that manifestations of mitochondrial dysfunction may vary among individuals, research into mitochondria provides a theoretical foundation for personalized medicine by allowing tailored treatment plans based on individual states of mitochondrial functionality [127].

[14] 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: 0.388) > 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.

[15] 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: 32
  • 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: 0.387) > 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.

[16] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.387) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[17] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[18] Novel Approaches to Studying SLC13A5 Disease

  • Authors: Adriana S. Beltran
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
  • DOI: 10.3390/metabo14020084
  • PMID: 38392976
  • PMCID: 10890222
  • Citations: 2
  • Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[19] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

  • Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
  • Year: 2024
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
  • DOI: 10.3389/fphar.2024.1397864
  • PMID: 38846086
  • PMCID: 11154008
  • Citations: 2
  • Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

[20] Chemotherapy and Mechanisms of Resistance in Breast Cancer

  • Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
  • Year: 2012
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
  • DOI: 10.5772/24629
  • Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

Notes

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