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Neurogenetics
Published in: neurogenetics 2/2020

01-04-2020 | Original Article

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

Authors: 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 Ługowska

Published in: Neurogenetics | Issue 2/2020

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Abstract

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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Metadata
Title
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
Authors
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 Ługowska
Publication date
01-04-2020
Publisher
Springer Berlin Heidelberg
Published in
Neurogenetics / Issue 2/2020
Print ISSN: 1364-6745
Electronic ISSN: 1364-6753
DOI
https://doi.org/10.1007/s10048-019-00600-6

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