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Dissecting the transcriptome of Parkin (PRKN)-linked Parkinson’s disease using 2D and 3D hiPSC-neuronal models

ABSTRACT: Mutations in the Parkin (PRKN) gene are the most common known cause of autosomal recessive early-onset Parkinson’s disease (PD), and Parkin dysfunction represents a risk factor for idiopathic PD. Parkin is an E3 ubiquitin ligase, involved in protein quality control and the removal of damaged mitochondria. Here, we generate human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic neurons using both a 2D differentiation protocol and our recently developed 3D method based on the microencapsulation of hiPSCs in small alginate/fibronectin beads. The transcriptional signature of cells from PD patients carrying PRKN mutations is evaluated at the neuronal stage and during the differentiation process. Analyses of mutation-specific gene sets and associated pathways reveal multiple biological processes implicated in PRKN-pathology, including synaptic and metabolic function, inflammation, and intracellular trafficking, reflecting a layered disease development. These data map the contribution of Parkin in early PD pathogenesis and progression before overt neurodegeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282152 | GEO | 2026/07/20

REPOSITORIES: GEO

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PARKIN is not required to sustain OXPHOS function in adult mammalian tissues

Project description:Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

2024-04-03 | GSE263057 | GEO

Transcriptomic alterations in fibroblasts from Parkinson's disease patients carrying Parkin mutations

Project description:In this study, we evaluate the hypothesis that transcriptome pattern of a cell model of Parkinson’s disease (PD) could be altered compared to healthy individuals. We cultured fibroblasts from Parkin-associated PD (PRKN-PD; n=4) and healthy controls (HC; n=4) and analysed the transcriptome profile by using whole RNA sequencing. We found 343 differentially expressed transcripts (DET) between patients and controls being 206 up-regulated and 137 down-regulated. These genes are related with the gene ontology terms cell adhesion, cell growth, aminoacid biosynthesis and folate metabolism amongst others. Our findings indicate that PRKN mutations are associated with global gene expression changes as observed in fibroblasts, and support an emerging view of PD as a systemic disease affecting also peripheral non-neural tissues such as the skin.

2018-03-05 | GSE90514 | GEO

Pathogenic pathways in early onset autosomal recessive Parkinson’s disease discovered using isogenic human dopaminergic neurons

Project description:Purpose of NGS transcriptomics: We generated RNA-sequencing transcriptomics datasets from isogenic Parkinson’s disease (PD) HUES1 cell lines (harboring loss of function mutations in either PARKIN (PRKN), DJ-1-/- (PARK7), or ATP13A2-/- (PARK9)) to identify common and distinct dysregulated genes and networks in our three isogenic PD lines in an unbiased way, with the goal of grouping similar and distinct forms of PD and identify common or divergent dysregulation.

2019-11-19 | GSE140076 | GEO

aCGH study of iPS cells from two normal subjects and two Parkinson's disease patients with parkin mutations

Project description:Parkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate that loss of parkin in human midbrain DA neurons greatly increases the transcription of monoamine oxidases and oxidative stress, significantly reduces DA uptake and increases spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescues these phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of DA neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD. Genomic DNA was isolated from each of the four lines of iPSCs and labeled with Cy5. Pooled sex mismatched normal human genomic DNA was labeled with Cy3. Both samples are hybridized together on RPCI 21K BAC aCGH array.

2012-01-21 | E-GEOD-35190 | biostudies-arrayexpress

A Next-Generation Sequencing Study in a Cohort of Patients with Parkinson’s Disease

Project description:Background: Parkinson’s disease (PD) is a multisystem and multifactorial disorder. Therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. Methods: We conducted a clinical-demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. Results: The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma, catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Conclusions: Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals.

2024-10-14 | E-MTAB-13523 | biostudies-arrayexpress

aCGH study of iPS cells from two normal subjects and two Parkinson's disease patients with parkin mutations

2012-01-21 | GSE35190 | GEO

Neural cell state modulation by PARK2 and dopaminergic neuroprotection by small molecule Parkin agonism [scRNA-seq]

Project description:Parkin, an E3 ubiquitin ligase encoded by PARK2, plays a key role in both hereditary and sporadic Parkinson’s disease (PD), yet there are no therapies currently available that can target this important pathway. Here, we show that Parkin is critical for successful neuronal differentiation and survival, and we develop small-molecule Parkin agonists that can protect dopaminergic neurons. Upon differentiation of neural progenitor cells, loss of Parkin results in a reduced capacity to maintain neuronal cell state, dopaminergic neuronal phenotypes, and stress resistance. Moreover, Parkin loss disrupted cell morphology and the stability of neurites. Transcriptional and single-cell analyses reveal that Parkin controls critical pathways regulating stem-like cell transitions and is needed for stable neuronal maturation. We also examined the effects of FB231, a small molecule enhancer of Parkin E3 ligase activity, in models of PD. FB231 reduced pathological α-synuclein and enhanced cell survival in human iPSC-derived dopaminergic neurons treated with α-synuclein preformed fibrils. Furthermore, FB231 attenuated α-synuclein pathology and dopaminergic neurodegeneration in a gut α-synuclein murine model of PD. Our findings support that Parkin plays a crucial role in maintaining neuronal homeostasis and that pharmacologic activation of Parkin may be a promising strategy to attenuate neurodegeneration in PD.

2026-07-13 | GSE337989 | GEO

Neural cell state modulation by PARK2 and dopaminergic neuroprotection by small molecule Parkin agonism [RNA-Seq]

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RNA-seq analysis of Parkin (Prkn) expression in wild-type and TKO mouse hearts under normal chow and high-fat diet [RNA-Seq]

Project description:High-fat diet (HFD) is known to promote metabolic stress and cardiac dysfunction. To examine genotype-dependent cardiac transcriptional responses, we performed RNA sequencing of hearts from wild-type (WT) and TKO mice fed either normal chow (NC) or a high-fat diet. RNA-seq analysis revealed significantly increased Parkin (Prkn) mRNA expression in TKO hearts compared with WT hearts under HFD conditions.

2026-01-30 | GSE317050 | GEO

A mutational atlas for Parkin

Project description:More than half of disease-causing missense variants are thought to lead to protein degradation, but the molecular mechanism of how these variants are recognized by the cell remains enigmatic. To approach this issue we have applied deep mutational scanning experiments to test the degradation of thousands of missense protein variants in large multiplexed experiments in cultured human cells. As a model protein we selected the ubiquitin-protein ligase Parkin, where known missense variants result in an autosomal recessive early onset Parkinsonism. The resulting mutational map comprises 9219 out of the 9300 (>99%) possible single-amino-acid substitution and nonsense Parkin variants. With a few notable exceptions, the majority of the destabilizing mutations are located within the structured domains of the protein, while the flexible linker regions are more tolerant to mutations. The cellular abundance data correlate with Parkin structural stability, evolutionary conservation, and separates known disease-linked variants from benign variants. Systematic mapping of degradation signals (degrons) shows that inherent primary degrons in Parkin largely overlap with regions that are highly sensitive to mutations. We identify a degron region proximal to the ACT element, which is enhanced by substitutions to hydrophobic residues. The vast majority of unstable Parkin variants are degraded through the ubiquitin-proteasome system and are stabilized at lowered temperatures. In conclusion, in addition to providing a diagnostic tool for rare genetic disorders, deep mutational scanning technologies have the potential to reveal both protein specific and general information on the specificity of the protein quality control network and the ubiquitin-proteasome system.

2024-01-31 | GSE254618 | GEO

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