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Transcriptome datasets of neural progenitors and neurons differentiated from induced pluripotent stem cells of healthy donors and Parkinson's disease patients with mutations in PARK2 gene

ABSTRACT: Parkinson's disease (PD) is a complex systemic disease caused by neurodegenerative processes in the brain, in which the death of dopaminergic neurons (DN) of the substantia nigra is primarily noted. 50% of cases of familial PD are associated with mutations in the PARK2 gene. Induced pluripotent stem cells (iPSCs) and their neuronal derivatives are powerful tool for disease modeling. Here, we presented the transcriptome profiles for neural progenitors (NP) and neurons, presumably DN, differentiated from iPSC lines of healthy donors and PARK2 mutations-associated PD patients generated on an NextSeq 500 System (Illumina). A comparative transcriptome analysis of neuronal derivatives of healthy donors and patients with PD will allow determining the contribution of mutations of the PARK2 gene to PD pathogenesis upon neuronal differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181029 | GEO | 2021/08/19

REPOSITORIES: GEO

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Project description:Mutations in PARK2 gene are the most frequent cause of familial forms of Parkinson’s disease (PD). This gene encodes Parkin, an E3 ubiquitin ligase involved in several cellular mechanisms, such as the mitophagic process. Mutations in this gene, which cause the loss of function of Parkin, are responsible for the accumulation of damaged mitochondria. This improper disposal may generate increased levels of ROS, lower ATP production and apoptosis activation. Given the importance of mitochondrial dysfunctions and mitophagy impairment in PD pathogenesis, the aim of the present project was to investigate both whole-cell and mitochondrial proteome alterations in human skin fibroblasts of PARK2-mutated patients. To this purpose, total and mitochondrial-enriched protein fractions from fibroblasts of five PARK2-mutated patients and five control subjects were analyzed by quantitative shotgun proteomics, in order to identify proteins specifically altered by Parkin loss. Both the network-based and the GSEA analysis of proteomics results pointed out the importance of pathways in which Rab GTPase proteins are involved. An alteration of their levels also in the mitochondrial fraction may indicate a re-localization of these GTP/GDP molecular switches, master regulators of membrane trafficking. To have a more comprehensive view of the mitochondrial alterations due to PARK2 mutations, we investigated the impact of Parkin loss on mitochondrial function and network morphology. We unveiled that the mitochondrial membrane potential was reduced in PARK2-mutated patients. Nevertheless, PINK1 did not accumulate on depolarized mitochondria. Even after the treatment with CCCP, an ionophore that triggers mitophagy, the accumulation of PINK1 was less efficient in PARK2-mutated patients than in controls derived fibroblasts. The analysis of the mitochondrial network morphology showed a filamentous network with mitochondria distributed all over the cell that was comparable between PARK2-mutated patients and control subjects. Thus, our results suggested that the network morphology was not influenced by the mitochondrial depolarization and by the lack of Parkin, revealing a possible impairment of fission and, more in general, of mitochondrial dynamics. In conclusion, the present work highlighted new molecular factors and pathways altered by PARK2 mutations. Furthermore, we obtained a definition of the mitochondrial landscape and molecular mechanisms underlying the PARK2 form of Parkinson’s disease, which will help to unravel possible biochemical pathways altered also in the sporadic form of the disease. Indeed, it is known that in sporadic cases the genetic/epigenetic background and the environment lead over time to mitochondria impairment and to the accumulation of damaged organelles.

Dataset Information

Transcriptome datasets of neural progenitors and neurons differentiated from induced pluripotent stem cells of healthy donors and Parkinson's disease patients with mutations in PARK2 gene

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