• This process depends on the endo-lysosomal sterol transfer protein Niemann Pick C2 (NPC2). (nature.com)
  • Using the intrinsically fluorescent cholesterol analog, cholestatrienol, we directly observe sterol transport to mitochondria in fibroblasts upon treating NPC2 deficient human fibroblasts with NPC2 protein. (nature.com)
  • NPC disease is caused by dysfunction of either the NPC1 or NPC2 protein. (nature.com)
  • The epididymal secretory protein E1, also known as NPC2( Niemann-Pick intracellular cholesterol transporter 2), is one of two main lysosomal transport proteins that assist in the regulation of cellular cholesterol by exportation of LDL-derived cholesterol from lysosomes. (wikipedia.org)
  • NPC2(or, alternatively, epididymal secretory protein E1) works cooperatively with the NPC1 protein to facilitate the exportation of LDL-derived cholesterol out of the lysosome to regulate the concentrations of lipids and cholesterol in the body. (wikipedia.org)
  • Epididymal secretory protein E1 is a protein associated with Niemann-Pick disease, type C, which is one of the 3 types of the Niemann-Pick diseases(Type A,B, and C). This disease can lead to an over accumulation of cholesterol and lipids in different types of tissues, including the brain. (wikipedia.org)
  • The epididymal secretory protein E1 is a small soluble glycoprotein consisting of 132 amino acids that is found in a large variety of cells. (wikipedia.org)
  • The epididymal secretory protein E1(NPC2) is produced via transcription of the NPC2 gene and recruits and transfers the LDL-derived cholesterol to the sterol-binding pocket in the N-terminal domain of the NPC1 protein to be transferred from the lysosome lumen and excreted from the lysosome membrane. (wikipedia.org)
  • Since the epididymal secretory protein E1 plays a role in the intracellular transport of cholesterol, a mutation in the gene that transcribes it(NPC2 gene) can cause serious issues that lead to Niemann-Pick disease, type C. Niemann-Pick disease, type C is a rare disorder that results in the over accumulation of lipids and cholesterol in different types of tissues in the body due to this protein being ubiquitous. (wikipedia.org)
  • We also study the NPC1 protein that is essential for cholesterol transport in humans and can lead to Niemann Pick C disease when mutated. (stanford.edu)
  • We also analyzed the evolutionary modularity of a data set of α -amylase catalytic domain homologs, and the dynamic modularity of the Niemann-Pick C1 (NPC1) protein N-terminal domain. (biomedcentral.com)
  • The NPC1 protein is involved in the intracellular lipid metabolism coordinating sterol trafficking. (biomedcentral.com)
  • Our inferred dynamic modules in the protein NPC1 are also shown to match functional components of the protein related to the NPC1 disease. (biomedcentral.com)
  • Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). (bvsalud.org)
  • Niemann Pick type C is an inborn error of metabolism (IEM), classified as a lysosomal storage disease (LSD) caused by a dysfunction in NPC transport protein, that leads to intracellular accumulation of non-esterified cholesterol and other lipids. (bvsalud.org)
  • Here, we asked whether this aberrant signaling may be exacerbated by the loss of amyloid precursor protein (APP) function, a loss known to shorten lifespan and accelerate neurodegeneration in Npc1 −/− mice. (biomedcentral.com)
  • Multiplex protein analysis further showed elevated expression of IP-10/CXCL10, a potent downstream effector of IFN-γ, as well as RANTES/CCL5, eotaxin/CCL11 and IL-10, prior to symptomatic onset in Npc1 −/− /App −/− cerebella, compared with Npc1 −/− /App +/+ mice. (biomedcentral.com)
  • When cellular cholesterol trafficking is interrupted, it can lead to fatal disorders, such as the neurodegenerative Niemann Pick type C (NPC) disease, in which cholesterol accumulates in late endosomes and lysosomes (LE/LYSs) and fails to reach the homeostatic sensing machinery in the ER 4 . (nature.com)
  • Niemann-Pick disease type C (NPC) is a progressive neurodegenerative condition that results in early fatality. (biomedcentral.com)
  • Niemann-Pick disease type C (NPC) is a neurodegenerative disease inherited in an autosomal recessive pattern [ 1 ], with mutations in the NPC1 gene accounting for approximately 95% of all reported cases and the remaining 5% of the cases resulting from mutations in the NPC2 gene. (biomedcentral.com)
  • Activating mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) cause Parkinson's disease and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al. (stanford.edu)
  • NPC is inherited in an autosomal recessive pattern from mutations in NPC1 or NPC2 genes. (biomedcentral.com)
  • It is caused by a mutation in the NPC2 gene that impairs the bodies ability to transport lipids or cholesterol intracellularly. (wikipedia.org)
  • At the cellular level, the disease phenotype is broad, affecting multiple functions, such as endosomal lipid accumulation, calcium dysregulation, neuroinflammation, mitochondrial dysfunction, amyloid peptide Aβ accumulation and tau hyperphosphorylation and aggregation. (biomedcentral.com)
  • NPC1 N-terminus is the first luminal domain which binds to cholesterol and its oxygenated derivatives. (biomedcentral.com)
  • Finally, investigation of HP-b-CD treatment was performed where we observe that, although HP-b-CD reduces cholesterol storage, levels of NPC1 and NPC2 are not normalized to control levels. (bvsalud.org)
  • We devise a protocol to determine the surface fraction of endo-lysosomes in contact with mitochondria and show that this fraction does not depend on functional NPC1 or NPC2 proteins. (nature.com)
  • We were able to describe functional/structural sub-domain architecture related to key residues for starch cleavage, calcium, and chloride binding sites in the α -amylase, and sterol opening-defining modules and disease-related residues in the NPC1. (biomedcentral.com)
  • NPC1 Low density lipoproteins Receptor mediated endocytosis Hypercholesterolemia Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL (October 2008). (wikipedia.org)
  • A molecular understanding of membrane traffic has broad implications for our understanding of growth control in cancer, receptor trafficking errors in heart disease, regulation of insulin secretion in diabetes and synaptic vesicle biogenesis and transport in neurological disorders. (stanford.edu)
  • Niemann-Pick, type C (NPC) is a fatal, neurovisceral lysosomal storage disorder with progressive neurodegeneration and no FDA-approved therapy. (bvsalud.org)
  • Lasting MCSs between endo-lysosomes containing NPC2 and mitochondria move by slow anomalous sub-diffusion, providing location and time for sterol transport between both organelles. (nature.com)
  • Niemann Pick Disease Type C". NORD (National Organization for Rare Disorders). (wikipedia.org)
  • Using fluorescence microscopy, we localize endo-lysosomes containing NPC2 relative to mitochondria based on the Euclidian distance transform and use statistical inference to show that about 30% of such LE/LYSs are in contact to mitochondria in human fibroblasts. (nature.com)
  • We have specifically shown an atypical activation pattern of interferon downstream signaling that involves both IFN-γ- and IFN-α-responsive genes in pre-symptomatic Npc1 −/− cerebella. (biomedcentral.com)
  • We have found that phosphorylation of Rab10 blocks primary cilia formation in culture and in certain brain regions and we would like to understand how this leads to Parkinson's disease. (stanford.edu)
  • LRRK2 that is hyperactive in some types of Parkinson's Disease specifically phosphorylates Rabs--we want to understand how this is linked to disease. (stanford.edu)
  • While NPC affects all cell types in the body, the main disease feature is the progressive neurodegeneration that results in premature death [ 1 ]. (biomedcentral.com)
  • Using Markov Chain Monte Carlo image simulations, we show that interaction between both organelle types, a defining feature of membrane contact sites (MCSs) can give rise to the observed spatial organelle distribution. (nature.com)
  • Niemann-Pick disease type C (NPC) is a rare, fatal, neurodegenerative lysosomal disease caused by mutations of either NPC1 or NPC2. (nih.gov)
  • NPC disease is caused by mutations in either the NPC1 (95% of cases) or NPC2 (5% of cases) genes, encoding the NPC1 and NPC2 proteins, respectively. (europa.eu)
  • NPC2 is a soluble lysosomal protein that functions in coordination with NPC1 to efflux cholesterol from the lysosomal compartment. (nih.gov)
  • While NPC1 is a transmembrane protein believed involved in retroendocytic shuttling of substrate(s) to the Golgi and possibly elsewhere in cells as part of an essential recycling/homeostatic control mechanism, NPC2 is a soluble lysosomal protein known to bind cholesterol. (nih.gov)
  • The precise role(s) of NPC1 and NPC2 in endosomal-lysosomal function remain unclear, nor is it known whether the two proteins directly interact as part of this function. (nih.gov)
  • The epididymal secretory protein E1, also known as NPC2( Niemann-Pick intracellular cholesterol transporter 2), is one of two main lysosomal transport proteins that assist in the regulation of cellular cholesterol by exportation of LDL-derived cholesterol from lysosomes. (wikipedia.org)
  • NPC1 is a 13 transmembrane domain protein of the late endosome and lysosome, while NPC2 is a soluble intra-lysosomal cholesterol transporter. (europa.eu)
  • Dietary restriction has shown promise for disorders such as lysosomal acid lipase deficiency (Wolman disease), as has incorporation of lipid-lowering drugs in the regimen along with sebelipase alpha, a recombinant enzyme replacement therapy. (medscape.com)
  • One of the most common lysosomal storage disorders is Gaucher disease, discussed below. (medscape.com)
  • Genetic deficiency of NPC1 or NPC2 results in a devastating cholesterol-glycosphingolipidosis of brain and other organs known as Niemann-Pick type C (NPC) disease. (nih.gov)
  • These studies have resulted in identifying specific disease-causing mutations and have led to improved clinical and laboratory diagnosis, prenatal diagnosis, and carrier identification. (medscape.com)
  • for example, Gaucher, Tay-Sachs, and Niemann-Pick type A are more common in Ashkenazi Jews, largely as a result of ancestral founder mutations. (medscape.com)
  • Patients who present in childhood tend to have more pronounced visceral and bony disease manifestations than those who present in adulthood. (medscape.com)
  • It is caused by a mutation in the NPC2 gene that impairs the bodies ability to transport lipids or cholesterol intracellularly. (wikipedia.org)
  • Using a CMA/mA fluorescence reporter we found that overexpression of wild-type UBQLN2 impairs CMA. (bvsalud.org)
  • BACKGROUND: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. (bvsalud.org)
  • Gaucher disease type 1 is less severe than type 2. (medscape.com)
  • [ 20 ] . Retinoblastoma has been noted in an infant with Gaucher disease. (medscape.com)
  • In addition, for some disorders (eg, Gaucher disease), making genotype-phenotype correlations that predict disease severity and allow more accurate genetic risk counseling is possible. (medscape.com)
  • 2) Determine the mechanism by which sterol accumulation inhibits NPC1 function and elucidate their role in regulating NPC1 activity. (europa.eu)
  • 1 Sidney Weisner Laboratory of Genetic Neurological Disease Department of Neuroscience, Rose F Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (nih.gov)
  • Juvenile-onset disease presents with ataxia and dysarthria and is not associated with a cherry-red spot of the macula. (medscape.com)
  • Complex form of disease ataxia reported amongst the phenotypic features in Citterio et al. (genomicsengland.co.uk)
  • Patients with infantile forms of Tay-Sachs disease present in infancy with loss of motor skills, increased startle reaction, and presence of a cherry-red spot on slit lamp examination. (medscape.com)
  • Niemann Pick Disease Type C". NORD (National Organization for Rare Disorders). (wikipedia.org)
  • This fellowship focused on elucidating the underlying cell biological mechanisms governing pathogenesis of the rare childhood disease Smith-Lemli-Opitz Syndrome (SLOS), for which there is currently no effective treatment. (europa.eu)
  • Approximately 6,500 rare diseases collectively affect some 26-30 million European citizens. (europa.eu)
  • Rare diseases therefore are an important research area, as very few are understood well enough to be treated effectively in the clinic. (europa.eu)
  • Situated within a leading Russell group university, the host laboratory has significant expertise in rare disease research, with an extensive collection of patient-derived cell lines and tissues, in addition to extensive experience in the specialist assays required for this research project. (europa.eu)
  • We have recently discovered a link at the cellular level between SLOS and another rare pediatric disease, Niemann-Pick C (NPC). (europa.eu)
  • Clinical manifestations of Sandhoff disease are similar to Tay-Sachs disease. (medscape.com)
  • In neurons from humans with NPC disease the metabolic defects and storage often lead to extensive growth of new, ectopic dendrites (possibly linked to ganglioside sequestration) as well as formation of neurofibrillary tangles (NFTs) (possibly linked to dysregulation of cholesterol metabolism). (nih.gov)
  • These include Tay-Sachs disease and Sandhoff disease. (medscape.com)
  • The pathologic features of NPC disease, however, are well documented. (nih.gov)