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Niemann-Pick Disease Type C

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Niemann-Pick Disease Type C. Core disease mechanisms, molecular and cellul...

2026-03-30
Asta MONDO:0018982 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Niemann-Pick Disease Type C. Core disease mechanisms, molecular and cellul...

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

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

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

  • Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
  • DOI: 10.3390/metabo14100515
  • PMID: 39452896
  • PMCID: 11509386
  • Citations: 2
  • Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
  • Evidence snippets:
  • Snippet 1 (score: 0.585) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[2] Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T

  • Authors: Maik Liedtke, Christin Völkner, Alexandra V. Jürs, Franziska Peter, M. Rabenstein et al.
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/dece27ded976e5c321087cfd5cfa52c3675a3fee
  • DOI: 10.3390/ijms22084009
  • PMID: 33924575
  • PMCID: 8069078
  • Citations: 4
  • Summary: A profile of pathophysiological in vitro features, shared byNP-C1 and NP-C2, of neural differentiated cells obtained from the patient specific iPSCs is presented, suggesting that they do not suffer from oxidative stress and express catalase at a high level.
  • Evidence snippets:
  • Snippet 1 (score: 0.558) > Niemann-Pick type C (NP-C) disease is a hereditary disease caused by mutations in the NPC1 or NPC2 gene. The proteins NPC1 and NPC2 accomplish the exclusion of cholesterol from late endosomes and lysosomes and are essential for maintaining cellular cholesterol homeostasis [1]. Consequently, mutations in NPC1 or NPC2 result in pathophysiological accumulation of cholesterol and sphingolipids in lysosomes and late endosomes. Comparison of clinical and biochemical phenotypes in human patients disclosed no qualitative difference, proving that NPC1 and NPC2 proteins are essential for the transport of cholesterol in lysosomal compartments in a cooperative manner [2]. Clinical manifestation of Niemann-Pick type C1 (NP-C1) disease and Niemann-Pick type C2 (NP-C2) disease share several commonalities; however, about 95% of NP-C patients show mutations of the NPC1 gene and only 5% harbor mutations of the NPC2 gene [3]. Naturally, the knowledge of the clinical presentation of NP-C1 is much more advances than the knowledge of NP-C2. Progression and severity of NP-C1 pathophysiology depends on the onset of the disease, wherein an early onset (early infantile form) is commonly linked to a severe phenotype with systemic involvement and an early demise of patients. An onset of NP-C1 in childhood (late infantile/juvenile form) or adulthood (adolescence/adult form) is frequently related to a neurological phenotype, although this cannot be considered as a generalized rule as the clinical presentation is heterogeneous and a clear genotype; phenotype correlation for NP-C1 is not given [3]. Regarding NP-C2, clinical case reports cite an early death of patients accompanied frequently with severe lung deficiencies [4]. Affected patients are mainly characterized by neurological dysfunction and liver damage. Neurological dysfunction causes many identifiable symptoms, including vertical supranuclear ophthalmoplegia, cataplexy, dysarthria, dysphagia, seizures, speaking and swallowing difficulty, and dementia [3].

[3] Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism?

  • Authors: E. Piscianz, L. Vecchi Brumatti, A. Tommasini, A. Marcuzzi
  • Year: 2019
  • Venue: Neural Regeneration Research
  • URL: https://www.semanticscholar.org/paper/60ed5edaa8b3b324f6d871c79d22e936ee02d6e4
  • DOI: 10.4103/1673-5374.247441
  • PMID: 30632494
  • PMCID: 6352582
  • Citations: 5
  • Influential citations: 1
  • Summary: Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.546) > Niemann-Pick disease is a very severe rare genetic disorder, which belongs to the family of lysosomal storage diseases, a condition that affects many body systems. Patients with Niemann-Pick disease cannot metabolize cholesterol and other lipids properly, leading to abnormal accumulation of these substances in liver, spleen and other organs (Guo et al., 2016). > Niemann-Pick disease presents a broad clinical spectrum, depending on the degree of defect in lipid trafficking. The onset can be at birth with a fatal disorder, or in children or even adults, with milder phenotypes characterized by progressive psychomotor impairment, in addition to liver and spleen enlargement. The defect of cholesterol trafficking to mitochondria is associated to mitochondrial dysfunction and impairment in antioxidant defense strategies. Moreover, besides the neurodegenerative aspect of the disease, Niemann-Pick disease phenotype implies systemic features since non-esterified cholesterol accumulate also in liver and spleen (Vanier, 1999(Vanier, , 2010;;Patterson et al., 2012). Different genetic forms of Niemann-Pick disease are known and, in particular, Niemann-Pick disease type C (NPC) is caused by mutations in NPC1 (OMIM #257220, 95% of cases) (Carstea et al., 1993(Carstea et al., , 1997) ) and NPC2 genes (OMIM #607625, 5% of cases) (Naureckiene et al., 2000) resulting in functional defects of proteins with lysosomal localization (Torres et al., 2017;Liu and Lieberman, 2018) that trigger an accumulation of non-degraded substrates that interferes with different cellular functions (Sarkar et al., 2013). These molecular mechanisms are not fully elucidated yet, and a deepen knowledge of these processes is of crucial importance because each step of the pathogenetic cascade in Niemann-Pick disease may be a potential target of therapy (Schultz et al., 2018;Wang et al., 2018).

[4] Metabolic Alteration Analysis of Steroid Hormones in Niemann–Pick Disease Type C Model Cell Using Liquid Chromatography/Tandem Mass Spectrometry

  • Authors: Ai Abe, Masamitsu Maekawa, Toshihiro Sato, Yu Sato, Masaki Kumondai et al.
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a31ba1a3e494b6af87a03ac9ea184c94a82802b9
  • DOI: 10.3390/ijms23084459
  • PMID: 35457276
  • PMCID: 9025463
  • Citations: 11
  • Summary: A comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC–MS/MS) and applied to analyze changes in steroid hormone concentrations in NPC model cells indicates that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities.
  • Evidence snippets:
  • Snippet 1 (score: 0.488) > Niemann-Pick disease type C (NPC) is an autosomal recessive disorder characterized by functional deficiencies affecting lysosomal cholesterol transport [1]. These deficits originate from a mutation in the NPC1 [2,3] or NPC2 genes [4,5], resulting in lipid accumulation [3,6] and the manifestation of various symptoms [1,[7][8][9]. The main symptoms associated with the systemic and central nervous system include hepatosplenomegaly, cholestasis, lung lesions, epilepsy, cognitive dysfunction, and ataxia [10]. Neuropathologically, it is characterized by progressive degeneration of nerve cells, particularly cerebellar Purkinje cells, and foam macrophage infiltration [11]. NPC therapeutic agents, such as miglustat and 2-hydroxypropyl-β-cyclodextrin, have been developed, and although the use of miglustat has been approved in some countries [12], 2-hydroxypropyl-β-cyclodextrin is still undergoing clinical trials [13]. Thus, despite various drug discovery approaches [14][15][16][17], clinical drug development has not yet been achieved. To date, the NPC pathology remains ambiguous, highlighting the necessity to explicate the associated underlying molecular mechanisms in an effort to overcome this disease. > Numerous studies have recently explored mitochondrial abnormalities in NPC. Briefly, these findings indicated that NPC-related lipid accumulation resulted in impaired autophagy, eventuating in abnormal mitochondrial activity [18][19][20][21]. Additionally, increased mitochondrial oxidative stress [22], downregulated ATP production [23], and reduced mitochondrial membrane potential have also been reported [24]. > Steroid hormones are vital bioactive metabolites derived from cholesterol, and are synthesized in the endoplasmic reticulum and mitochondria [25][26][27].

[5] Practical recommendations for diagnosis, management, and follow-up of Niemann-Pick type-C disease patients: a Brazilian perspective

  • Authors: D. Horovitz, A. Pessoa, Marcondes Cavalcanti França Júnior, Roberto Giugliani, C. F. Souza et al.
  • Year: 2024
  • Venue: Arquivos de Neuro-Psiquiatria
  • URL: https://www.semanticscholar.org/paper/f04b5f111939b479cc92ac171b23af0365ee772e
  • DOI: 10.1055/s-0045-1807714
  • PMID: 40345672
  • PMCID: 12064313
  • Citations: 2
  • Influential citations: 1
  • Summary: Recommendations include patient characteristics on clinical presentation, as systemic and neurological manifestations according to the age group and atypical manifestations; a flowchart for diagnostic confirmation, considering the Brazilian scenario; and treatment, encompassing disease-modifying therapy, supportive care, and patients' follow-up.
  • Evidence snippets:
  • Snippet 1 (score: 0.486) > Niemann-Pick type-C (NPC) disease is a rare genetic condition, caused by biallelic pathogenic variants in homozygosity or compound heterozygosity in any of two genes (NPC1 and NPC2) that encode proteins involved in the intralysosomal cholesterol trafficking. The clinical spectrum ranges from a fatal prenatal disorder to an adult-onset, chronic, neurodegenerative disease. The rare prevalence of the disease and the lack of specialized care lead to misdiagnosis or late diagnosis, in addition to barriers to proper care. Such aspects contribute to physical, psychological, and intellectual impairments, resulting in major disability. 1 Niemann-Pick type-C disease is a rare condition with an estimated incidence of 1 case per 100,000 live births. The disease is pan-ethnic, and pathogenic variants in the NPC1 gene cause at least 95% of all cases. 2 Burton et al. ( 2021) conducted a study to determine the disease prevalence in the United States and estimated 2.9 cases per million inhabitants. 3 The minimal incidence for Brazil was calculated as 0.304/100,000. 4 iemann-Pick type-C disease has a complex physiopathology, starting from a simple failure of cholesterol export, progressing via multiple pathways to affect numerous cellular functions and results leading to early cellular death. This multi-faceted pathology poses a difficult challenge to develop therapies for this disorder. 5 To date, as it happens with other rare disorders, no specific curative therapy is available, and NPC disease usually progresses to premature death. Miglustat, a substrate-reducing therapy, is the only disease-modifying drug approved in Brazil for treating neurological manifestations, attenuating, or even stopping disease progression. 7][8][9] The most recently published document proposes the use of supportive therapies in addition to miglustat for all patients with a confirmed diagnosis, except for those presymptomatic or presenting only an enlarged spleen or liver. In addition, diagnostic guidelines have been proposed. 8 ven the scarcity of information regarding NPC in Brazil, a group of experts was invited to discuss some disease-related aspects at the national level.

[6] δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders*

  • Authors: Miao Xu, Ke Liu, M. Swaroop, F. Porter, Rohini Sidhu et al.
  • Year: 2012
  • Venue: The Journal of Biological Chemistry
  • URL: https://www.semanticscholar.org/paper/5cc1f90c4676e68745524d4add44afc26b907f68
  • DOI: 10.1074/jbc.M112.357707
  • PMID: 23035117
  • Citations: 126
  • Influential citations: 6
  • Summary: The data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.479) > Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that ␦-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a ␦-tocopherol-induced intracellular Ca 2؉ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that ␦-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases. > Niemann-Pick disease type C (NPC) 3 is caused by mutations in either the NPC1 or NPC2 gene, encoding two distinct lysosomal cholesterol-binding proteins (1,2). The NPC cellular phenotype is characterized by lysosomal accumulation of unesterified cholesterol and other lipids, resulting from impaired cholesterol export from the late endosomal and lysosomal compartments (2,3). Wolman disease is caused by mutations in the gene encoding lysosomal acid lipase (LAL). Deficiency of LAL function results in two distinct disease phenotypes that accumulate

[7] Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

  • Authors: S. Torres, Elisa Balboa, S. Zanlungo, C. Enrich, C. Garcia-Ruiz et al.
  • Year: 2017
  • Venue: Frontiers in Physiology
  • URL: https://www.semanticscholar.org/paper/fee7f30e342ac595aa3e669ce33743baa695f1f3
  • DOI: 10.3389/fphys.2017.00982
  • PMID: 29249985
  • PMCID: 5714892
  • Citations: 73
  • Influential citations: 2
  • Summary: A better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.469) > Niemann-Pick (NP) diseases encompass a group of autosomal recessive lysosomal storage disorders (LSD), characterized by the accumulation of diverse lipid species in lysosomes. While these diseases were initially considered a single entity with overlapping biochemical, pathological and clinical features, developing evidence demonstrated differential etiological causes (Patterson and Walkley, 2017;Schuchman and Desnick, 2017). Niemann-Pick type A and B (NPA and NPB) diseases are caused by deficits in the activity of acid sphingomyelinase (ASMase), an enzyme that regulates lysosomal sphingomyelin (SM) homeostasis, while Niemann-Pick type C (NPC) disease is caused by mutations in NPC1 and NPC2 genes, resulting in functional defects in the lysosomal proteins NPC1 and NPC2, involved in cholesterol efflux from lysosomes. > Although the primary consequence of ASMase inactivation results in the accumulation of lysosomal SM, cholesterol and other lipids types, such as bis(monoacylglycero)phosphate, glucocerebroside, GM2 and GM3 gangliosides and sphingosine also accumulate in lysosomes (Rodriguez-Lafrasse et al., 1994;Vanier, 2013;Schuchman and Desnick, 2014). Similarly, although in NPC disease cholesterol accumulation is the direct consequence of NPC1/NPC2 loss of function, SM and other sphingolipids, such as lactosylceramide, glucosylceramide, GM2 and GM3 gangliosides and sphingosine, accumulate as well (Pentchev et al., 1984;Lloyd-Evans et al., 2008;Patterson et al., 2012). Hence, these findings imply that the trafficking and metabolism of different lipid species through the endocytic pathway are severily affected in these lysosomal diseases, likely contributing to their pathogenesis. However, the molecular mechanisms and signaling pathways responsable for cell death and tissue damage in these diseases are not entirely clear.

[8] Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1

  • Authors: Christin Völkner, Maik Liedtke, A. Hermann, M. Frech
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/34258d343bc77def5ce926bad7f201ab6597cf02
  • DOI: 10.3390/ijms22020710
  • PMID: 33445799
  • PMCID: 7828283
  • Citations: 9
  • Summary: The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark. A total of 95% of cases are due to a deficiency of NPC1 and onl...
  • Evidence snippets:
  • Snippet 1 (score: 0.466) > Niemann-Pick disease type C is a rare monogenic neurovisceral lysosomal storage disorder, inherited in an autosomal recessive manner, with an estimated incidence of 1/120,000 [1]. Homozygous or compound heterozygous mutations in the NPC1 (95%; OMIM # 257220) or NPC2 (5%, OMIM # 607625) gene lead to impaired intracellular transport of cholesterol and glycosphingolipids, resulting in the accumulation of these lipids in late endosomes/lysosomes (LE/LY). Currently, 549 mutations in NPC1 and 29 mutations in NPC2 have been described [2]. The location of observed mutations is not limited to the cholesterol binding site; rather, they can be found throughout the whole sequence and can lead to misfolded protein, resulting in proteasomal degradation and hampered trafficking to the lysosome and therefore reduced lipid turnover. Clinical manifestations of patients do not show a strong genotype-phenotype correlation, but rather Niemann-Pick disease type C is characterized by heterogeneous phenotypic expression. Therefore, it is hardly possible to predict the clinical outcome caused by a specific mutation, suggesting that several factors may be involved in the pathogenesis of the disease. > The clinical spectrum of NPC1 includes visceral manifestations, such as hepatosplenomegaly, and neurological symptoms, such as hypotonia, loss of motor skills, ataxia, seizures, dysphagia, dysarthria, supranuclear gaze palsy (VSGP), and dementia, as well as psychiatric symptoms. Systemic and neurological symptoms occur at different times, with systemic symptoms, which may be absent in 10-15% of cases, preceding neurological symptoms. The age of onset of symptoms defines the classification into perinatal, infantile (early and late), juvenile, and adolescent/adult forms of NPC1.

[9] Biomarkers in Lysosomal Storage Diseases

  • Authors: Joaquín Bobillo Lobato, Maria Jiménez Hidalgo, L. M. Jiménez Jiménez
  • Year: 2016
  • Venue: Diseases
  • URL: https://www.semanticscholar.org/paper/6a8bdc58db4d91dd2efe5adec28c651c2a2a41aa
  • DOI: 10.3390/diseases4040040
  • PMID: 28933418
  • PMCID: 5456325
  • Citations: 34
  • Influential citations: 1
  • Summary: The most promising biomarkers in major LSDs are summarized and discussed and why these are the most promising candidates for screening systems are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.465) > The term "Niemann-Pick disease" (NP) includes a heterogeneous group of lysosomal lipid accumulation diseases with clinical, biochemical, and molecular features. > In 1961, Crocker classified them into four subgroups (types A-D) [49]. In types A and B (OMIM 257200, 607616; prevalence of 0.25 and 0.4/100,000 [12] respectively), the accumulation of sphingomyelin in different organs and tissues is due to a deficit of acid sphingomyelinase enzyme (ASM; EC 3.1.4.12) caused by mutations in the sphingomyelin phosphodiesterase-1 gene. In types C and D (OMIM 257220, 1/100,000 prevalence) [12] however, a defect in cellular lipid transport can result in several pathological forms of the disorder [50]. > We now know that NP-C disease is clinically, biochemically, and genetically distinct from types A and B. The NP-D disease is an allelic variant of type C found only in patients in Nova Scotia (Canada). > As in most lysosomal storage disorders, the clinical spectrum of Niemann-Pick disease A/B is increasingly regarded as a continuum from the most severe to relatively mild presentation [51]. > Acid sphingomyelinase plays a major role in sphingolipid metabolism, because it catalyzes the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Ceramide and related products (such as sphingosine-1-phosphate) are involved in a variety of molecular and cellular processes, and play a central role in a growing number of human diseases [52]. The ASM deficiency in Niemann-Pick disease types A and B causes the accumulation of sphingomyelin and other lipids in various tissues, mainly in the monocyte-macrophage system. > Until recently, sphingomyelin was the only biomarker available for the disease. Although its levels have been shown to be elevated more than 10-fold in the livers and spleens of NP-B patients, levels in plasma have been found to overlap those of normal controls [53].

[10] Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

  • Authors: E. Uribe-Carretero, Verónica Rey, J. M. Fuentes, Isaac Tamargo-Gómez
  • Year: 2024
  • Venue: Biology
  • URL: https://www.semanticscholar.org/paper/170a8e8c7d82acd3f25b107a238b3ae439337661
  • DOI: 10.3390/biology13010034
  • PMID: 38248465
  • PMCID: 10813815
  • Citations: 8
  • Summary: Insight into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, is provided, and recent advancements and breakthroughs in this field are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.463) > Niemann-Pick type C (NPC) disease is a genetic autosomal recessive lysosomal storage disorder caused by mutations in either NPC1 (95% of cases) or NPC2 (5% of cases). These genes encode proteins involved in the intracellular trafficking of lipids and cholesterol [225]. Mutations in these genes result in the accumulation of unesterified cholesterol in the liver, spleen, and brain, which, in turn, disrupts lipid transport. In fact, these alterations cause a disruption that leads to the loss of Purkinje cells in the cerebellum and degeneration of other components of the central nervous system [226]. > From a clinical perspective, NPC is typically a disease with juvenile or later onset, and the rate of progression inversely correlates with the age of onset. Common symptoms of NPC include ataxia, splenomegaly, hepatomegaly, hypotonia, severe liver disease, respiratory infections, and abnormal eye movements [227]. > In this context, there is an alteration of the autophagic mechanism in NPC, as an accumulation of autophagosomes in skin fibroblasts from NPC patients is described. In the molecular landscape of this disease, this accumulation is partially due to the function of BECN1 and LC3B. In wild-type fibroblasts, their levels increase when exposed to U18666A, a small molecule used to induce NPC-like lipid trafficking defects. Moreover, NPC exhibits a blocked autophagic flux due to impaired autophagosome maturation [228] and specific defects in mitophagy [229]. > Therefore, autophagy is significantly disrupted in NPC. This disruption interferes in the maintenance of cellular and tissue homeostasis, contributing to the pathological changes observed in NPC patients. The accumulation of autophagosomes, their impaired maturation, and the defective mitochondrial function all contribute to the disease's progression, affecting cellular and tissue health.

[11] Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

  • Authors: M. E. López, M. Scott
  • Year: 2013
  • Venue: Disease Models & Mechanisms
  • URL: https://www.semanticscholar.org/paper/88ebd1599676b2ea0ad531fbaca09899ec5b970b
  • DOI: 10.1242/dmm.012385
  • PMID: 23907005
  • PMCID: 3759329
  • Citations: 24
  • Summary: Progress in mouse-model-based studies of NPC disease is reviewed, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking.
  • Evidence snippets:
  • Snippet 1 (score: 0.452) > Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC) is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

[12] Case Report: Be Aware of “New” Features of Niemann–Pick Disease: Insights From Two Pediatric Cases

  • Authors: Fan Chen, Shan Guo, Xuesong Li, Shengxuan Liu, L. Wang et al.
  • Year: 2022
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/0e90092e587e5a751cb719feea6600be63ee7e7d
  • DOI: 10.3389/fgene.2022.845246
  • PMID: 35360843
  • PMCID: 8961870
  • Citations: 2
  • Summary: The findings suggest that immune activation should be considered as a “new” clinical phenotype of lysosomal storage diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.444) > Lysosomal storage diseases (LSDs) comprise a group of more than 70 distinct genetic diseases. LSDs are characterized by the accumulation of undigested macromolecules in lysosomes of various body cells. Although these disorders are rare, they affect 1 in 5,000 live births, accounting for 14% of all inherited metabolic diseases. LSDs have similar clinical features despite different pathogenetic mechanisms (Rigante et al., 2017;Platt et al., 2018). Niemann-Pick disease is a relatively common autosomal recessive LSD. Clinical manifestations and pathogenic genes are mainly classified into types A, B, and C (Vanier, 2013). Niemann-Pick disease type C (NPC) is a progressive and fatal disorder caused by mutations in the NPC1 (OMIM 257220) or NPC2 (OMIM 607625) gene, which results in the intracellular accumulation of unesterified cholesterol. As cholesterol accumulates in cells, it affects the brain, liver, spleen, and lungs, leading to premature death. The estimated incidence of NPC is 1:100,000, with variable age of onset and clinical features (Vanier, 2010;Patterson et al., 2012;Geberhiwot et al., 2018). Perinatal manifestations of NPC often include splenomegaly, hepatomegaly, fetal ascites, or nonimmune fetal hydrops (Spiegel et al., 2009;Surmeli-Onay et al., 2013). Severe hepatic diseases, associated or not with pulmonary disease, are neonatal manifestations of NPC (Bjurulf et al., 2008;Griese et al., 2010). In comparison with the adult period, cholestatic liver disease is a typical clinical phenotype in infants. However, some affected infants may also present hypotonia and developmental delay with little hepatic and pulmonary involvement (Vanier et al., 1988).

[13] Complex N-Linked Glycosylation: A Potential Modifier of Niemann–Pick Disease, Type C1 Pathology

  • Authors: N. Cawley, Anna T. Lyons, D. Abebe, Rachel Luke, Julia Yerger et al.
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/1aef8b0292ef503509b14727e6f7384549321396
  • DOI: 10.3390/ijms23095082
  • PMID: 35563467
  • PMCID: 9103943
  • Citations: 6
  • Summary: The results suggest that reduced asparagine-linked glycosylation increases NPC1 disease severity in mice, and leads to the hypothesis that mutations in genes involved in asparagin- linked glycosolation may contribute to disease severity progression in individuals with NPC1.
  • Evidence snippets:
  • Snippet 1 (score: 0.437) > Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative lysosomal disorder. It is inherited in an autosomal recessive manner and occurs with an estimated incidence of 1:100,000 to 1:150,000 births [1,2]. Patients have pathological variants in either NPC1 (95% of cases) or NPC2, which code for proteins involved in the binding and efflux of unesterified cholesterol out of the late endosome/lysosome compartments [3,4]. Pathological variants in either gene results in the accumulation of unesterified cholesterol and glycosphingolipids within the late endosomal/lysosomal system [5,6]. This eventually leads to cellular dysfunction, and in the case of the cerebellum, to the degeneration of Purkinje neurons [7]. The clinical phenotype of this disease is marked by hepatosplenomegaly, cerebellar ataxia, and progressive cognitive decline [1]. Early death of the patient ultimately occurs [8]. > As a key organelle in the progression of NPC, the integrity and function of the lysosome, and its limiting membrane, is critical. The lysosomal membrane is of particular interest, where the complexity and integrity of the ~8 nm glycocalyx [9] is important since increased lysosomal membrane permeability has been shown to occur in microglia, resulting in the leakage of hydrolytic enzymes, such as cathepsin B, and cell death [10]. Heat shock protein 70 (HSP70) has been shown to stabilize lysosomal membrane permeability as part of its pro-survival mechanism [11,12]. Thus, Arimoclomol TM , a drug currently undergoing clinical trials for treatment of NPC1, which induces HSP70, is proposed to stabilize the lysosomal membrane in NPC1 as part of its mechanism of action.

[14] A human neuronal model of Niemann Pick C disease developed from stem cells isolated from patient’s skin

  • Authors: N. Bergamin, A. Dardis, A. Beltrami, D. Cesselli, S. Rigo et al.
  • Year: 2013
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/aa4c61fb8788db926e8f667a45cb81e436149315
  • DOI: 10.1186/1750-1172-8-34
  • PMID: 23433359
  • PMCID: 3648447
  • Citations: 36
  • Influential citations: 2
  • Summary: A human neuronal model of NPC disease is generated through the induction of differentiation of stem cells obtained from patient’s easily accessible sources and may be applied to easily generate human neuronal models of other neurodegenerative diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.435) > Niemann Pick C [NPC-MIM 257220; MIM607625] disease is a neurodegenerative lysosomal storage disorder due to mutations in NPC1 or NPC2 genes, characterized by the accumulation of endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosomes/late endosomes. Both proteins are involved in the intracellular trafficking of cholesterol and other lipids. Thus, the deficiency of either of them leads to the accumulation of the endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosome/late endosome compartment [1]. > Clinically, NPC disease presents a highly variable phenotype ranging from fetal to adult age. Even though initial manifestations are typically systemic, including liver and spleen enlargement, the disease has been classified according to the age at onset of neurological symptoms in: severe infantile form (onset before 2 y of age), late infantile form (onset between 3-5 y of age), juvenile form (onset between 5 and 16 y) and adult form (onset at age>16 y) [1,2]. > Approximately 95% of NPC patients present mutations in NPC1 gene (MIM 607623; chr 18q11-q12) [3,4], which encodes a membrane glycoprotein of 1,278 amino acids containing 13 transmembrane domains and localized in late endosomes [5]. The other 5% of patients present mutations in NPC2 gene (MIM 601015; chr 14q24.3) [6] encoding a soluble 151 amino acid protein that is present in the lumen of lysosomes. > Despite the progress in characterizing the biochemical and genetic defects in NPC disease, the mechanisms underlying the pathophysiology of this disorder are not clear and the currently available therapeutic interventions are limited. In particular, the analysis of the molecular pathways linking the lipid accumulation and cellular damage in the brain has been challenging due to the limited availability of neuronal models. > Two mouse models of NPC disease have been described and used to study NPC pathogenesis, the BALB

[15] Necroptosis in neurodegenerative diseases: a potential therapeutic target

  • Authors: Shuo Zhang, Mi-bo Tang, Hai-yang Luo, Changhe Shi, Yu-ming Xu
  • Year: 2017
  • Venue: Cell Death & Disease
  • URL: https://www.semanticscholar.org/paper/ef425bdd135e925a09d44e21fac8ffab70314905
  • DOI: 10.1038/cddis.2017.286
  • PMID: 28661482
  • PMCID: 5520937
  • Citations: 166
  • Influential citations: 6
  • Summary: The present review is aimed at summarizing the molecular mechanisms of necroPTosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.431) > Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal lipid storage disorder with progressive neurodegeneration. 79 NPC is classified as type C1 (NPC1) or type C2 (NPC2), which are caused by mutations in the NPC1 or NPC2 genes, respectively. Mutations in the NPC1 gene account for 95% of NPC patients. 80 Degeneration of cerebellar Purkinje neurons is a prominent early feature in the disease progression, which leads to clinical symptoms of motor impairments. 81 Very little is known about the cellular death mechanisms leading to neuronal loss in NPC1, and thus the potential efficacy of cell death inhibitors remains unexplored. A recent study reported that activation of the necroptotic pathway contributes to neuronal death in NPC1 82 The expression level of RIP1 and RIP3 are raised with the formation of the necrosome in NPC1 fibroblasts. 82 Consist with the results in NPC1-mutant mice and human patients brain tissue, thus strongly suggesting that necroptosis has a pathological role in NPC1. 82 Of note, the formation of the necrosomal complex appeared to be more prominent in fibroblast lines from subjects with age adjusted neurological severity scores 83 less than or equal to 1.5. 82 Indicates that activation of the necroptotic pathway may be correlate with disease severity. > The mechanism by mutant NPC1 influences the disease are not fully understood. It is clear that necroptosis activation occurs during NPC1 progression, with an abundance of RIP1 and RIP3 found in NPC1 fibroblasts and post-mortem brain tissue of NPC patients compared to controls. 82 Treatment of NPC1 fibroblasts from NPC1 patient with Nec-1 or suppression of either RIP1 or RIP3 expression can significant suppress cell death. 82 Treatment of Npc1 − / − mice with Nec-1 resulted in delayed cerebellar Purkinje cell loss, delayed progression of neurological manifestations and significantly prolonged lifespan. 82 These results provide a strong link between necroptosis with the molecular mechanism that contributes to neuronal loss in NPC1.

[16] Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature

  • Authors: J. Sheth, Jijo John Joseph, K. Shah, M. Muranjan, M. Mistri et al.
  • Year: 2017
  • Venue: BMC Medical Genetics
  • URL: https://www.semanticscholar.org/paper/c16e1b25dd6dfaceb68774d5ee7fd79da15df977
  • DOI: 10.1186/s12881-017-0367-x
  • PMID: 28095804
  • PMCID: 5240394
  • Citations: 25
  • Influential citations: 1
  • Summary: This study demonstrates that NPC2 can present in early years of life with pulmonary complications like alveolar proteinosis and hepatosplenomegaly or hepatomeGaly due to mutation in NPC2 gene.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Niemann-Pick disease type C (NPC) is a fatal autosomal recessive neurovisceral disorder due to mutation in NPC1 and NPC2 genes leading to alterations in trafficking of endocytosed cholesterol [1]. Due to heterogeneous clinical phenotype, NPC is underdiagnosed and often missed altogether. In NPC, the protein product of the NPC1 gene functions as a transporter of cholesterol and glycolipids in the endosomal-lysosomal system whereas the smaller protein product of NPC2 cooperates with the NPC1 protein [2,3]. NPC2 plays a vital role in endosomal/ lysosomal cholesterol trafficking by markedly accelerating the rates of transport from and between membranes [4]. The mechanism of NPC2 action involves direct interaction of the protein with membranes. The defects in NPC1 and NPC2 proteins, leads to sequestration of cholesterol derived products in the cell leading to hepatosplenomegaly, pulmonary and neurological manifestations [3]. NPC1 gene is responsible for 95% of manifestations with main phenotype being hepatosplenomegaly and nervous system. The other ~5% of the NPC is caused by NPC2 gene where pulmonary manifestations with respiratory failure have been documented [5]. Till date nearly twenty cases have been reported of NPC2 with twelve homoallelic mutations and none from India. Present study is the first report of NPC2 from India with primary pulmonary manifestations and hepatosplenomegaly highlighting phenotype-genotype correlation.

[17] Elevation of plasma lysosphingomyelin-509 and urinary bile acid metabolite in Niemann-Pick disease type C-affected individuals

  • Authors: R. Mashima, Masamitsu Maekawa, A. Narita, T. Okuyama, N. Mano
  • Year: 2018
  • Venue: Molecular Genetics and Metabolism Reports
  • URL: https://www.semanticscholar.org/paper/bd3ee59c4f6a9a7c023644d5336f745cbf938514
  • DOI: 10.1016/j.ymgmr.2018.03.005
  • PMID: 30023294
  • PMCID: 6047109
  • Citations: 14
  • Influential citations: 1
  • Summary: The efficacy of plasma SPC and lysosphingomyelin-509 as promising biomarkers for this disorder was supported by the finding that the urinary concentration of 3β-sulfooxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid, an established biomarker for NPC, was also elevated in the NPC-affected individuals.
  • Evidence snippets:
  • Snippet 1 (score: 0.429) > Niemann-Pick disease type C (NPC) is a neurovisceral disorder caused by a defective mutation in either the NPC1 (OMIM 607623) or the NPC2 (OMIM 601015) gene [1,2]. The impaired egress of cholesterol from the late endosome/lysosomal compartment has been suggested to be a relevant mechanism for the pathogenesis of NPC. Early evidence showed consistently that NPC was associated with the accumulation of various lipids, including cholesterol in humans [3]. These lipids include a variety of cholesterol metabolites such as oxysterol, including cholestane-3β,5α,6β-triol and 7-ketocholesterol [4][5][6][7][8][9], bile acids [10][11][12][13][14], and glucosylated cholesterol [15], respectively. The NPC1 protein is a membraneous protein in the lysosome, which facilitates the transportation of cholesterol from the lysosome to plasma membrane, whereas NPC2 is a soluble protein in the lysosome, which binds stoichiometrically to cholesterol. Based on these biochemical properties of NPC1 and NPC2, the mechanism(s) of NPC might be, at least partly, attributed to the failure of proper lipid trafficking in the cells [2]. This possibility was evidenced in several murine NPC models that showed positive therapeutic outcomes on the established NPC manifestations by treatment with cyclodextrin, a circular oligosaccharide that facilitates cholesterol transportation across the plasma membrane [16][17][18]. A recent study revealed the prevalence of classical NPC is 1/89,229, while the incidence of late-onset NPC incompletely predicted [19]. > Both clinical and experimental evidence have indicated that the level of sphingomyelin is increased in NPC in the liver and spleen [2,3]. In mammals, the biosynthesis of sphingomyelin is initiated by serine https [20]. Sphingomyelin is

[18] The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase

  • Authors: C. Fog, P. Zago, E. Malini, Lukasz M. Solanko, P. Peruzzo et al.
  • Year: 2018
  • Venue: EBioMedicine
  • URL: https://www.semanticscholar.org/paper/38f5b73dd632f30a0cfff54f8068f4a69253fd8e
  • DOI: 10.1016/j.ebiom.2018.11.037
  • PMID: 30497978
  • PMCID: 6306395
  • Citations: 42
  • Summary: Data demonstrate the potential of HSP-targeting therapies in GCase-deficiencies and strongly support the clinical development of arimoclomol as a potential therapeutic option for the neuronopathic forms of GD.
  • Evidence snippets:
  • Snippet 1 (score: 0.429) > Our results demonstrate that arimoclomol is a heat shock protein amplifying small molecule that may be useful for the treatment of Gaucher disease including its neuronopathic forms which have no approved treatments available. > In these studies we have focused on ex vivo systems in order to address the fundamental concept of HSP-mediated refolding across the major genotypes of Gaucher disease and investigating the biological rationale for clinical development of arimoclomol for neuronopathic Gaucher disease. > We demonstrate that arimoclomol amplifies the production of disease mechanism-relevant molecular chaperones of the HSP70 family and improves mutant GCase maturation and function across major neuronopathic and non-neuronopathic genotypes in both human primary GD fibroblasts as well as in a neuronal cellular model of the disease. > As arimoclomol is a clinically enabled compound already in phase II/ III clinical trials for Niemann-Pick disease type C, sporadic Inclusion Body Myositis and Amyotrophic Lateral Sclerosis (Clinicaltrials.gov identifiers NCT02612129, NCT02753530, and NCT03491462 respectively), the data reported herein provide preclinical proof-of-concept for the investigation of arimoclomol's therapeutic value in Gaucher disease. > While it is a known challenge to translate doses from in vitro studies to a human clinical setting, let alone across diseases, the arimoclomol doses used herein are congruent with the doses used for the preclinical studies in the sphingolipid storage disease Niemann-Pick type C (Kirkegaard et al., Science Transl. Med. 2016 and manuscript in prep.) which recently reported encouraging top-line results from a phase III clinical trial. Furthermore, the same type of in vitro studies has formed basis for the development of the recently approved drug migalastat, a small chemical chaperone developed for misfolded versions of the enzyme alpha-galactosidase A, in the sphingolipid storage disease Fabry disease (https://www.fda.gov/newsevents/newsroom/ pressannouncements/uc

[19] Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

  • Authors: Elisa Balboa, T. Marín, J. E. Oyarzún, Pablo S Contreras, R. Hardt et al.
  • Year: 2021
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/208ed0f3ffeefd13edf13d4abe6cb9f9aa435123
  • DOI: 10.3390/cells10082159
  • PMID: 34440927
  • PMCID: 8392304
  • Citations: 11
  • Influential citations: 1
  • Summary: This study found potential therapeutic targets for the treatment of liver damage in NPCD by analyzing hepatocytes derived from wild type and Npc1−/− mice by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis.
  • Evidence snippets:
  • Snippet 1 (score: 0.427) > Niemann Pick type C disease (NPCD) is a neurovisceral lysosomal storage disorder (LSD) with an estimated incidence of 1/90,000 live births [1]. It is caused by mutations in the NPC1 or NPC2 genes, which encode lysosomal cholesterol transport proteins that mediate free cholesterol efflux from this compartment. Therefore, NPC1 or NPC2 deficient cells accumulate cholesterol in lysosomes. The most affected tissues are the central nervous system (CNS) and the liver [2]. The symptoms and clinical presentation are extremely heterogeneous, with age of onset ranging from the perinatal period to adulthood. Visceral involvement includes the liver, spleen, and sometimes the lungs, while possible neurological disorders consist mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. The onset of systemic symptoms frequently precedes the start of neurological symptoms [3]. Although most patients with NPCD die from complications of the neurological disorder [3], some also develop fatal liver disease [4]. Aside from liver failure [5,6], NPC patients frequently present with neonatal jaundice (52%), enlargement of the spleen (36%), liver (31%), and ascites (19%) [7]. At the organ and tissue levels, mice lacking the NPC1 protein (NPC mice) develop liver disease with hepatomegaly, cell death, infiltration of foamy macrophages, inflammation, proliferation of hepatic stellate cells, and fibrosis [8][9][10]. > Usually, the systemic disease is not very severe, except for the perinatal period in which a small subset of patients die in the first six months of life [3]. Given the hepatic manifestations in the development of NPCD and to design treatments for liver symptoms that will provide a better quality of life for patients, it is necessary to understand the molecular pathways that are affected in NPC liver cells. > Proteomics technology is a tool that allows full-scale analysis of all proteins involved in a pathological process.

[20] Retinal axonal degeneration in Niemann–Pick type C disease

  • Authors: J. Havla, M. Moser, C. Sztatecsny, Amelie S Lotz-Havla, E. Maier et al.
  • Year: 2020
  • Venue: Journal of Neurology
  • URL: https://www.semanticscholar.org/paper/f4fe3e3da2fd6b506a1f05e1779558a264469c45
  • DOI: 10.1007/s00415-020-09796-2
  • PMID: 32222928
  • PMCID: 7320959
  • Citations: 23
  • Summary: Using OCT, retinal degeneration in NPC1-P and significant correlation between retinal neuroaxonal degeneration with clinical measurements was shown and OCT may be an important marker of neurodegeneration in NPCs1-disease after onset of clinical symptoms.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > Niemann-Pick disease type C (NPC) is an autosomal recessively inherited neurovisceral lysosomal disorder caused by mutations in the NPC1 or NPC2 gene [1,2]. The clinical phenotype ranges from an infancy-onset progressive, fatal disorder to an adult-onset, chronic neurodegenerative disease with heterogeneous clinical symptoms such as cognitive impairment, cerebellar symptoms, dystonia, vertical supranuclear saccade and gaze palsy, psychiatric disorders, and, less frequently, epilepsy [3]. Optic nerve pallor and perimacular gray discoloration are observed ophthalmologically, as well as histologically [4]. However, markers reflecting disease progression in NPC are not well established. Pathophysiologically, NPC is characterized by abnormalities of intracellular transport of endocytosed cholesterol and further lipids with their sequestration in lysosomes and late endosomes [5,6]. Notably, dysregulation of brain cholesterol homeostasis is also present in some of the common neurodegenerative central nerve system (CNS) disorders Tatiana Bremova-Ertl and Susanne A. Schneider have contributed equally to this work. such as Alzheimer`s disease (AD) and Parkinson's disease (PD) [7][8][9]. In addition, NPC and AD share common pathophysiological mechanisms such as neurofibrillary tangle formation, increased amyloidogenic amyloid precursor protein (APP), early development of endosome abnormalities, and neuronal death [10][11][12][13]. Optical coherence tomography (OCT) is a non-invasive, cost-effective, and widely used imaging technique of the retinal layers introduced in the last few years as a potential marker of neurodegeneration in various neuroinflammatory and neurodegenerative disorders [14,15].

Notes

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