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

  • Katarzyna Hetmańczyk-Sawicka
  • Roksana Iwanicka-Nowicka
  • Anna Fogtman
  • Jarosław Cieśla
  • Paweł Włodarski
  • Barbara Żyżyńska-Granica
  • Mirella Filocamo
  • Andrea Dardis
  • Paolo Peruzzo
  • Małgorzata Bednarska-Makaruk
  • Marta Koblowska
  • Agnieszka ŁugowskaEmail author
Original Article


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.


Niemann–Pick C disease NPC1 Microarray qRT-PCR Expression 



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:, 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.

Author contributions

K.H-S.: experimental work, data analysis and drafted the manuscript; R.I-N.: experimental work and data analysis; A.F.: experimental work and data analysis; J.C.: data analysis; B.Ż-G.: experimental work and data analysis; P.W.: revised the manuscript; M.F.: experimental work and drafted and revised the manuscript; A.D.: experimental work and drafted and revised the manuscript; P.P.: experimental work; M.B-M.: performed the statistical analysis, drafted and revised the manuscript; M.K.: experimental work, data analysis and revised the manuscript; A.Ł.: conception of the project, design, data interpretation, drafted and revised the manuscript. All authors revised and approved the final version of the manuscript.

Funding information

This work was supported by Narodowe Centrum Nauki ( 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’ ( to MF.

Compliance with ethical standards

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.

Competing interests

The authors declare that they have no competing interests.

Supplementary material

10048_2019_600_MOESM1_ESM.docx (2.7 mb)
ESM 1 (DOCX 2813 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Katarzyna Hetmańczyk-Sawicka
    • 1
  • Roksana Iwanicka-Nowicka
    • 2
    • 3
  • Anna Fogtman
    • 2
  • Jarosław Cieśla
    • 4
  • Paweł Włodarski
    • 5
  • Barbara Żyżyńska-Granica
    • 6
  • Mirella Filocamo
    • 7
  • Andrea Dardis
    • 8
  • Paolo Peruzzo
    • 8
  • Małgorzata Bednarska-Makaruk
    • 1
  • Marta Koblowska
    • 2
    • 3
  • Agnieszka Ługowska
    • 1
    Email author
  1. 1.Department of GeneticsInstitute of Psychiatry and NeurologyWarsawPoland
  2. 2.Laboratory of Microarray Analysis, Institute of Biochemistry and BiophysicsPolish Academy of SciencesWarsawPoland
  3. 3.Laboratory of Systems Biology, Faculty of BiologyUniversity of WarsawWarsawPoland
  4. 4.Institute of Biochemistry and BiophysicsPolish Academy of SciencesWarsawPoland
  5. 5.Center for Preclinical Research, Department of MethodologyMedical University of WarsawWarsawPoland
  6. 6.Department of Biochemistry, Second Faculty of Medicine with the English Division and the Physiotherapy DivisionMedical University of WarsawWarsawPoland
  7. 7.Laboratorio di Genetica Molecolare e BiobancheIstituto G. GasliniGenoaItaly
  8. 8.Regional Coordinator Centre for Rare Diseases, Department of Laboratory MedicineAcademic Hospital “Santa Maria della Misericordia” UdineUdineItaly

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