Sporadic Parkinson’s disease derived neuronal cells show disease-specific mRNA and small RNA signatures with abundant deregulation of piRNAs

Abstract

Differentiated neurons established via iPSCs from patients that suffer from familial Parkinson’s disease (PD) have allowed insights into the mechanisms of neurodegeneration. In the larger cohort of patients with sporadic PD, iPSC based information on disease specific cellular phenotypes is rare. We asked whether differences may be present on genomic and epigenomic levels and performed a comprehensive transcriptomic and epigenomic analysis of fibroblasts, iPSCs and differentiated neuronal cells of sporadic PD-patients and controls. We found that on mRNA level, although fibroblasts and iPSCs are largely indistinguishable, differentiated neuronal cells of sporadic PD patients show significant alterations enriched in pathways known to be involved in disease aetiology, like the CREB-pathway and the pathway regulating PGC1α. Moreover, miRNAs and piRNAs/piRNA-like molecules are largely differentially regulated in cells and post-mortem tissue samples between control- and PD-patients. The most striking differences can be found in piRNAs/piRNA-like molecules, with SINE- and LINE-derived piRNAs highly downregulated in a disease specific manner. We conclude that neuronal cells derived from sporadic PD-patients help to elucidate novel disease mechanisms and provide relevant insight into the epigenetic landscape of sporadic Parkinson’s disease as particularly regulated by small RNAs.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0561-x) contains supplementary material, which is available to authorized users.

Drosophila melanogaster as a Model to Study the Multiple Phenotypes, Related to Genome Stability of the Fragile-X Syndrome

“…Aging represents a risk factor for the occurrence of sporadic PD (Martin, 2011). piRNAs and piRNA-like molecules are differentially expressed in “induced Pluripotent Stem Cells” (iPSCs) from patients during differentiation (Schulze et al., 2018).…”

Small Non-coding RNAs: New Class of Biomarkers and Potential Therapeutic Targets in Neurodegenerative Disease

“…Patient tissue samples showed the same trend, with 70 different piRNAs overlapping between both (Table 3). Two distinct trends come from these piRNAs, up or down regulation (Schulze et al, 2018). In the down-regulated piRNA fraction, those that were short-interspersed nuclear elements (SINE) and long-interspersed nuclear elements (LINE) derived elements in cell lines and LINE in tissues, showed significant enrichment when compared to genome-wide expression (Schulze et al, 2018).…”

“…Two distinct trends come from these piRNAs, up or down regulation (Schulze et al, 2018). In the down-regulated piRNA fraction, those that were short-interspersed nuclear elements (SINE) and long-interspersed nuclear elements (LINE) derived elements in cell lines and LINE in tissues, showed significant enrichment when compared to genome-wide expression (Schulze et al, 2018). This is indicative of an inability to silence SINE and LINE derived elements in PD-derived neurones, which could show a pathogenesis of PD disease.…”

Using induced pluripotent stem cells for modeling Parkinson’s disease

“…piRNA is a complex of piwi protein and RNA, and is a large class of small noncoding RNA molecules expressed in animal cells that are involved in the epigenetic and post-transcriptional silencing of transposons. Schulze et al[82] have shown that the specific alteration of sin- and line-derived piRNA in DA neurons could be a new mechanism for the causation of PD[82-84].…”