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-SawickaRoksana Iwanicka-NowickaAnna FogtmanJarosław CieślaPaweł WłodarskiBarbara Żyżyńska-GranicaMirella FilocamoAndrea DardisPaolo PeruzzoMałgorzata Bednarska-MakarukMarta KoblowskaAgnieszka ŁugowskaPublished in: Neurogenetics (2020)
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.
Keyphrases
- oxidative stress
- poor prognosis
- cell proliferation
- signaling pathway
- end stage renal disease
- endoplasmic reticulum stress
- cell death
- immune response
- newly diagnosed
- extracellular matrix
- ejection fraction
- gene expression
- chronic kidney disease
- peritoneal dialysis
- cognitive impairment
- dna damage
- cell cycle arrest
- genome wide
- prognostic factors
- pi k akt
- ischemia reperfusion injury
- rheumatoid arthritis
- long non coding rna
- convolutional neural network
- deep learning
- dna methylation
- diabetic rats
- blood brain barrier
- early onset
- brain injury
- replacement therapy
- patient reported
- smoking cessation