Dataset Information

¬Single cell transcriptomics of human iPSC differentiation dynamics reveal a core network of Parkinson’s disease

ABSTRACT: Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons obtained through differentiation of human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1 and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson’s disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, validating the manifestation of the affected neuronal phenotype. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers new interpretation of the phenotypic heterogeneity of PD.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: Gunnar Dittmar

LAB HEAD: Gunnar Dittmar

PROVIDER: PXD028283 | Pride | 2022-02-15

REPOSITORIES: pride

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			Action	DRS
	Qplus_00029245_MQQC_HS_SR_Skupin11.raw	Raw
	Qplus_00029246_MQQC_HS_SR_Skupin12.raw	Raw
	Qplus_00029247_MQQC_HS_SR_Skupin13.raw	Raw
	Qplus_00029248_MQQC_HS_SR_Skupin14.raw	Raw
	Qplus_00029249_MQQC_HS_SR_Skupin15.raw	Raw

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Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson's disease.

Novak Gabriela G Kyriakis Dimitrios D Grzyb Kamil K Bernini Michela M Rodius Sophie S Dittmar Gunnar G Finkbeiner Steven S Skupin Alexander A

Communications biology 20220113 1

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA se ...[more]

PMID: 35027645

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Project description:Background: Parkinson’s disease (PD) is a progressive, degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal deficits, including soft monotone speech, result in significant clinical and quality of life issues and are present in 90% of PD patients; yet, the underlying pathology mediating these significant voice deficits is unknown. The Pink1-/- rat is a valid model of early-onset PD that presents with analogous vocal communication deficits (e.g. reduced loudness). Previous work shows abnormal α-synuclein protein aggregation in the periaqueductal gray (PAG), a brain region critical and necessary to the modulation of mammalian vocal behavior. In this study, we used high-throughput RNA sequencing to examine gene expression within the PAG of both male and female Pink1-/- rats as compared to age-matched wildtype controls. We used a bioinformatic approach to (1) test the hypothesis that loss of Pink1 in the PAG will influence expression of genes that interact with Pink1, (2) highlight other key genes that relate to Mendelian PD, and (3) catalog molecular targets important for the production of rat vocalizations. Results: Knockout of the Pink1 gene resulted in differentially expressed genes for both male and female rats. Pathway analysis highlighted several significant metabolic pathways. Weighted gene co-expression network analysis (WGCNA) was used to identify gene nodes and their interactions in (A) males, (B) females, and (C) combined-sexes datasets. For each analysis, within the module containing the Pink1 gene, Pink1 itself was the central node with the highest number of interactions with other genes including solute carriers, glutamate metabotropic receptors, and genes associated with protein localization. Strong connections between Pink1 and Krt2 and Hfe were found in both males and female datasets. In females a number of modules were significantly correlated with vocalization traits. Of interest, gene enrichment of the key vocal Cyan module in females showed a significant number of neuromodulatory genes including Nts, Slc6a4, Slc10a4, Ndnf, and Gpr160, that may be responsible for the modulation of rat vocalizations. The top biological pathways within the female Cyan vocal module included the regulation of membrane depolarization, indolalkylamine metabolic process, and monoamine transport. Conclusions: Overall, this work supports the premise that gene expression changes in the PAG may contribute to the vocal behavioral and deficits observed in this PD rat model. Additionally, this dataset identifies genes that represent new therapeutic targets for PD voice disorders.