Transcriptome Analysis of Induced Pluripotent Stem Cells and Neuronal Progenitor Cells, Derived from Discordant Monozygotic Twins with Parkinson’s Disease

Abstract

Parkinson’s Disease (PD) is a widespread severe neurodegenerative disease that is characterized by pronounced deficiency of the dopaminergic system and disruption of the function of other neuromodulator systems. Although heritable genetic factors contribute significantly to PD pathogenesis, only a small percentage of sporadic cases of PD can be explained using known genetic risk factors. Due to that, it could be inferred that changes in gene expression could be important for explaining a significant percentage of PD cases. One of the ways to investigate such changes, while minimizing the effect of genetic factors on experiment, are the study of PD discordant monozygotic twins. In the course of the analysis of transcriptome data obtained from IPSC and NPCs, 20 and 1906 differentially expressed genes were identified respectively. We have observed an overexpression of TNF in NPC cultures, derived from twin with PD. Through investigation of gene interactions and gene involvement in biological processes, we have arrived to a hypothesis that TNF could play a crucial role in PD-related changes occurring in NPC derived from twins with PD, and identified INHBA, WNT7A and DKK1 as possible downstream effectors of TNF.

Transcription of HOX Genes Is Significantly Increased during Neuronal Differentiation of iPSCs Derived from Patients with Parkinson’s Disease

“…Moreover, the qPCR analysis of RNA in NPCs and TDNs from PD patients with other mutations ( GBA, PARK8, and GBA + PARK8 ) ( Figure 5 ) also showed the activation of HOX cluster genes, especially in NPCs, thus demonstrating the more general nature of this process. Additional analysis of our previously published data on DEGs in sporadic cases of PD in twins [ 40 ] showed the increased expression level of some HOX genes in NPCs from one more PD patient ( Figure S7 ). However, it should be noted that such an association was not always observed.…”

“…However, it should be noted that such an association was not always observed. NPCs and TDNs derived from PD1 patient iPSC did not reveal HOX gene expression as well as a differential expression of HOX genes was not detected in the NPCs from one other patient with a sporadic case of PD in twins compared with that in HD ( Figure S7 [ 40 ]). Thus, in neuronal cell lines obtained from 6 out of 8 PD patients, a significant increase in the expression of a number of HOX genes at the level of transcription was revealed.…”

An Efficient 2D Protocol for Differentiation of iPSCs into Mature Postmitotic Dopaminergic Neurons: Application for Modeling Parkinson’s Disease

“…All neurons from our set are located inside the mature neuron cluster among neurons from all sets with neurons. In our analysis, iPSCs originated from only two datasets, and according to their protocols, two clusters have been formed, namely set51 [ 36 ] of 2 samples and set64 of 12 samples [ 38 ]. The clustering of iPSCs may reflect differences in protocols for generating and culturing cells in different laboratories.…”

Transcriptome Profiling Reveals Differential Expression of Circadian Behavior Genes in Peripheral Blood of Monozygotic Twins Discordant for Parkinson’s Disease

“…We are also actively conducting whole-transcriptome studies of different cell types of monozygotic twins discordant for PD and not carrying mutations associated with this disease. To date, data on the study of fibroblasts [ 26 ], as well as iPSC and NCP [ 27 ], have already been published. In this work, we carried out an RNA-seq analysis of the peripheral blood.…”

“…Dulovic-Mahlow et al investigated mitochondrial phenotypes in skin fibroblast cultures from five pairs of monozygotic twins discordant for PD [ 25 ]. In addition, in our previous studies, a whole transcriptome analysis was performed in the fibroblasts [ 26 ], as well as in the iPSCs and neuronal progenitor cells (NPCs) [ 27 ], of monozygotic twins discordant for PD. However, studies on the analysis of transcriptomic profiling of the peripheral blood of such twins have not been conducted yet.…”