Changes in gene expression profiles were investigated in 23 patients with Niemann–Pick C1 disease (NPC). cDNA expression microarrays with subsequent validation by qRT-PCR were used. Comparison of NPC to control samples revealed upregulation of genes involved in inflammation (MMP3, THBS4), cytokine signalling (MMP3), extracellular matrix degradation (MMP3, CTSK), autophagy and apoptosis (CTSK, GPNMB, PTGIS), immune response (AKR1C3, RCAN2, PTGIS) and processes of neuronal development (RCAN2). Downregulated genes were associated with cytoskeletal signalling (ACTG2, CNN1); inflammation and oxidative stress (CNN1); inhibition of cell proliferation, migration and differentiation; ERK-MAPK pathway (COL4A1, COL4A2, CPA4); cell adhesion (IGFBP7); autophagy and apoptosis (CDH2, IGFBP7, COL4A2); neuronal function and development (CSRP1); and extracellular matrix stability (PLOD2). When comparing NPC and Gaucher patients together versus controls, upregulation of SERPINB2 and IL13RA2 and downregulation of CSRP1 and CNN1 were characteristic. Notably, in NPC patients, the expression of PTGIS is upregulated while the expression of PLOD2 is downregulated when compared to Gaucher patients or controls and potentially could serve to differentiate these patients. Interestingly, in NPC patients with (i) jaundice, splenomegaly and cognitive impairment/psychomotor delay—the expression of ACTG2 was especially downregulated; (ii) ataxia—the expression of ACTG2 and IGFBP5 was especially downregulated; and (iii) VSGP, dysarthria, dysphagia and epilepsy—the expression of AKR1C3 was especially upregulated while the expression of ACTG2 was downregulated. These results indicate disordered apoptosis, autophagy and cytoskeleton remodelling as well as upregulation of immune response and inflammation to play an important role in the pathogenesis of NPC in humans.
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Geberhiwot T, Moro A, Dardis A et al (2018) International Niemann-pick disease registry (INPDR). Consensus clinical management guidelines for Niemann-pick disease type C. Orphanet J Rare Dis 13:50. https://doi.org/10.1186/s13023-018-0785-7
Wraith JE, Baumgartner MR, Bembi B et al (2009) Recommendations on the diagnosis and management of Niemann-pick disease type C. Mol Genet Metab 98:152–165
Spiegel R, Raas-Rothschild A, Reish O et al (2009) The clinical spectrum of fetal Niemann-pick type C. Am J Med Genet A 149A:446–450
Patterson MC, Clayton P, Gissen P et al (2017) Recommendations for the detection and diagnosis of Niemann-pick disease type C. Neurol Clin Pract 7:499–511
Li X, Saha P, Li J et al (2016) Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2. Proc Natl Acad Sci U S A 113(36):10079–10084
Wheeler S, Schmid R, Sillence DJ (2019) Lipid–protein interactions in Niemann–pick type C disease: insights from molecular modeling. Int J Mol Sci 20(3):717
Kwon HJ, Abi-Mosleh L, Wang ML et al (2009) Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137:1213–1224
Vanier MT (2015) Complex lipid trafficking in Niemann-pick disease type C. J Inherit Metab Dis 38:187–199
Walkley SU (2007) Pathogenic mechanisms in lysosomal disease: a reappraisal of the role of the lysosome. Acta Pediatr S96:26–32
te Vruchte D, Lloyd-Evans E, Veldman RJ et al (2004) Accumulation of glycosphingolipids in Niemann-pick C disease disrupts endosomal transport. J Biol Chem 279:26167–26175
Lusa S, Blom TS, Eskelinen EL et al (2001) Depletion of rafts in late endocytic membranes is controlled by NPC1-dependent recycling of cholesterol to the plasma membrane. J Cell Sci 114:1893–1900
Wolf Z, Orso E, Werner T, Kluenemann HH, Schmitz G (2007) Monocyte cholesterol homeostasis correlates with the presence of detergent resistant membrane microdomains. Cytometry A71:486–494
Vitner EB, Platt FM, Futerman AH (2010) Common and uncommon pathogenic cascades in lysosomal storage diseases. J Biol Chem 285:20423–20427
Lloyd-Evans E, Morgan AJ, He X et al (2008) Niemann-pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med 14:1247–1255
Lloyd-Evans E, Platt FM (2010) Lipids on trial: the search for the offending metabolite in Niemann-pick type C disease. Traffic 11:419–428
Smith D, Wallom KL, Williams IM, Jeyakumar M, Platt FM (2009) Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-pick disease type C1. Neurobiol Dis 36:242–251
Liao G, Yao Y, Liu J et al (2007) Cholesterol accumulation is associated with lysosomal dysfunction and Autophagic stress in Npc1−/− mouse brain. Am J Pathol 171:962–975
Ishibashi S, Yamazaki T, Okamoto K (2009) Association of autophagy with cholesterol-accumulated compartments in Niemann-pick disease type C cells. J Clin Neurosci 16:954–959
Pacheco CD, Kunkel R, Lieberman AP (2007) Autophagy in Niemann-pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum Mol Genet 16:1495–1503
Rabenstein M, Peter F, Joost S, Trilck M, Rolfs A, Frech MJ (2017) Decreased calcium flux in Niemann-pick type C1 patient-specific iPSC-derived neurons due to higher amount of calcium-impermeable AMPA receptors. Mol Cell Neurosci 83:27–36
Cluzeau CVM, Watkins-Chow DE, Fu R et al (2012) Microarray expression analysis and identification of serum biomarkers for Niemann–pick disease, type C1. Hum Mol Genet 21:3632–3646
Vazquez MC, del Pozo T, Robledo FA et al (2011) Alteration of gene expression profile in Niemann-pick type C mice correlates with tissue damage and oxidative stress. PLoS One 6:e28777. https://doi.org/10.1371/journal.pone.0028777
Reddy JV, Ganley IG, Pfeffer SR (2006) Clues to neuro-degeneration in Niemann-pick type C disease from global gene expression profiling. PLoS One 1:e19. https://doi.org/10.1371/journal.pone.0000019
de Windt A, Rai M, Kytömäki L et al (2007) Gene set enrichment analyses revealed several affected pathways in Niemann-pick disease type C fibroblasts. DNA Cell Biol 26:665–671
Rauniyar N, Subramanian K, Lavallée-Adam M et al (2015) Quantitative proteomics of human fibroblasts with I1061T mutation in Niemann-pick C1 (NPC1) protein provides insights into the disease pathogenesis. Mol Cell Proteomics 14(7):1734–1749
Filocamo M, Mazzotti R, Corsolini F et al (2014) Cell line and DNA biobank from patients affected by genetic diseases. Open J bioresources 1: e2, DOI. https://doi.org/10.5334/ojb.ab
Ługowska A, Hetmańczyk-Sawicka K, Iwanicka-Nowicka R et al (2019) Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes. Sci Rep 9:6060. https://doi.org/10.1038/s41598-019-42584-1
Alam MS, Getz M, Yi S et al (2014) Plasma signature of neurological disease in the monogenetic disorder Niemann-pick type C. J Biol Chem 289(12):8051–8066
Newton J, Hait NC, Maceyka M et al (2017) FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-pick type C mutant fibroblasts. FASEB J 31(4):1719–1730
Falk T, Garver WS, Erickson RP et al (1999) Expression of Niemann-pick type C transcript in rodent cerebellum in vivo and in vitro. Brain Res 839(1):49–57
Li H, Repa JJ, Valasek MA et al (2005) Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-pick type C disease. J Neuropathol Exp Neurol 64:323–333
Praggastis M, Tortelli B, Zhang J et al (2015) A murine Niemann-pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J Neurosci 35(21):8091–8106
Krämer A, Green J, Pollard J Jr, Tugendreich S (2014) Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30:523–530
Szklarczyk D, Gable AL, Lyon D et al (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47(D1):D607–D613
Lawler J, McHenry K, Duquette M, Derick L (1995) Characterization of human thrombospondin-4. J Biol Chem 270:2809–2814
Falo MC, Fillmore HL, Reeves TM, Phillips LL (2006) Matrix metalloproteinase-3 expression profile differentiates adaptive and maladaptive synaptic plasticity induced by traumatic brain injury. J Neurosci Res 84:768–781
Morita-Fujimura Y, Fujimura M, Gasche Y, Copin JC, Chan PH (2000) Overexpression of copper and zinc superoxide dismutase in transgenic mice prevents the induction and activation of matrix metalloproteinases after cold injury-induced brain trauma. J of Cerebral Blood Flow and Metabolism 20:130–138
Gurney KJ, Estrada EY, Rosenberg GA (2006) Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol Dis 23:87–96
Yokoyama C, Yabuki T, Inoue H et al (1996) Human gene encoding prostacyclin synthase (PTGIS): genomic organization, chromosomal localization, and promoter activity. Genomics 36:296–304
Gelb BD, Willner JP, Verloes A, Herens C, Desnick RJ (1997) Mutation analysis of pycnodysostosis reveals uniparental disomy of chromosome 1. Am J hum genet 61 suppl: A28
Asagiri M, Hirai T, Kunigami T et al (2008) Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 319:624–627
Littlewood-Evans AJ, Bilbe G, Bowler WB et al (1997) The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res 57:5386–5390
Khanna M, Qin KN, Wang RW, Cheng KC (1995) Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases. J Biol Chem 270:20162–20168
Matsuura K, Shiraishi H, Hara A et al (1998) Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity. J Biochem 124:940–946
Miwa T, Manabe Y, Kurokawa K et al (1991) Structure, chromosome location, and expression of the human smooth muscle (enteric type) gamma-actin gene: evolution of six human actin genes. Mol Cell Biol 11:3296–3306
Liu R, Jin J-P (2016) Calponin isoforms CNN1, CNN2 and CNN3: regulators for actin cytoskeleton functions in smooth muscle and non-muscle cells. Gene 585:143–153
Soininen R, Haka-Risku T, Prockop DJ, Tryggvason K (1987) Complete primary structure of the alpha 1-chain of human basement membrane (type IV) collagen. FEBS Lett 225:188–194
Liebhaber SA, Emery JG, Urbanek M, Wang XK, Cooke NE (1990) Characterization of a human cDNA encoding a widely expressed and highly conserved cysteine-rich protein with an unusual zinc-finger motif. Nucleic Acids Res 18:3871–3879
Erdel M, Weiskirchen R (1999) Assignment1 of CSRP1 encoding the LIM domain protein CRP1, to human chromosome 1q32 by fluorescence in situ hybridization. Cytogenet Cell Genet 83:10–11
Wu J, Reinhardt DP, Batmunkh C et al (2006) Functional diversity of lysyl hydroxylase 2 in collagen synthesis of human dermal fibroblasts. J Exp Cell Res 312:3485–3494
Schneider VA, Granato M (2007) Genomic structure and embryonic expression of zebrafish lysyl hydroxylase 1 and lysyl hydroxylase 2. Matrix Biol 26:12–19
Walker LC, Overstreet MA, Yeowell HN (2005) Tissue-specific expression and regulation of the alternatively-spliced forms of lysyl hydroxylase 2 (LH2) in human kidney cells and skin fibroblasts. Matrix Biol 23:515–523
Seranova E, Connolly KJ, Zatyka M et al (2017) Dysregulation of autophagy as a common mechanism in lysosomal storage diseases. Essays Biochem 61:733–749
Bajaj L, Lotfi P, Pal R, Ronza AD, Sharma J, Sardiello M (2019) Lysosome biogenesis in health and disease. J Neurochem 148:573–589
Liu EA, Lieberman AP (2019) The intersection of lysosomal and endoplasmic reticulum calcium with autophagy defects in lysosomal diseases. Neurosci Lett 697:10–16
Pacheco CD, Elrick MJ, Lieberman AP (2009) Tau normal function influences Niemann-pick type C disease pathogenesis in mice and modulates autophagy in NPC1-deficient cells. Autophagy 5:548–550
Malnar M, Hecimovic S, Mattsson N, Zetterberg H (2014) Bidirectional links between Alzheimer's disease and Niemann-pick type C disease. Neurobiol Dis 72(Pt A):37–47
Platt N, Speak AO, Colaco A et al (2016) Immune dysfunction in Niemann-pick disease type C. J Neurochem 136(Suppl 1):74–80
Cologna SM, Cluzeau CVM, Yanjanin NM et al (2014) Human and mouse neuroinflammation markers in Niemann-pick disease, type C1. J Inherit Metab Dis 37:83–92
Yan X, Lukas J, Witt M et al (2011) Decreased expression of myelin gene regulatory factor in Niemann-pick type C 1 mouse. Metab Brain Dis 26:299–306
Alam MS, Getz M, Safeukui I et al (2012) Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder. PLoS One 7(10):e48273. https://doi.org/10.1371/journal.pone.0048273
Ba L, Z-j L, B-t B, Wang W, Zhang M (2017) Aberrant activation of Cdc2/cyclin B1 is involved in initiation of cytoskeletal pathology in murine Niemann-pick disease type C. Curr Med Science 37:732–739
Bu B, Klunemann H, Suzuki K et al (2002) Niemann-pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles. Neurobiol Dis 11:285–297
Lee JA, Yerbury JJ, Farrawell N et al (2015) SerpinB2 (PAI-2) modulates Proteostasis via binding misfolded proteins and promotion of Cytoprotective inclusion formation. PLoS One 10:e0130136. https://doi.org/10.1371/journal.pone.0130136
The authors would like to thank physicians, patients and their families for the co-operation as well as Dr. B. Goryluk for her valuable contribution to the work.
Role of the funding source
Sponsors had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Data availability statement
All data underlying the results described in this article are fully available without restriction at the NCBI’s Gene Expression Omnibus (GEO, http: www.ncbi.nlm.nih.gov/geo, GEO Series accession number GSE124283) or are within the article and its Supplementary Information files, Online Resource ESM 1. In the case of any additional questions, authors will be able to share any requested documents, methods or data.
This work was supported by Narodowe Centrum Nauki (https://www.ncn.gov.pl) Grant No. 2012/07/B/NZ1/02615 to AŁ, KH-S, RI-N, AF, PW and MK and partially supported by unrestricted grants from ‘Cinque per mille e Ricerca Corrente, Ministero della Salute’ (www.salute.gov.it) to MF.
Following ethical guidelines, all cell and nucleic acid samples were obtained for analysis and stored with the patients’ (and/or a family member’s) written informed consent. The protocol and procedures of this study were accepted by the local Bioethics Committee at the Institute of Psychiatry and Neurology (Warsaw, Poland). All experiments were performed in accordance with relevant guidelines and regulations.
The authors declare that they have no competing interests.
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Hetmańczyk-Sawicka, K., Iwanicka-Nowicka, R., Fogtman, A. et al. Changes in global gene expression indicate disordered autophagy, apoptosis and inflammatory processes and downregulation of cytoskeletal signalling and neuronal development in patients with Niemann–Pick C disease. Neurogenetics (2020) doi:10.1007/s10048-019-00600-6
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