Induced pluripotent stem cell (iPSC) technology is widely used to model complex diseases in cases where it is challenging to access injury sites or culture post-mortem tissues, such as neurodegenerative disorders and cardiac illness. One of the major challenges in biomarker discovery and drug development of neurodegenerative disorders is that their molecular mechanism is poorly understood. iPSC-derived models offer a unique opportunity to gain an in-depth understanding of disease etiology and the molecular factors contributing to disease progression.
By harnessing bulk RNA-seq data from patient-derived iPSC models, we can effectively facilitate biomarker discovery, surmounting challenges inherent in the use of animal models such as inter-species omic differences, variations in brain cell types, and neuronal network disparities.
This 'Monthly Dataset Roundup' presents notable bulk RNA-seq datasets of iPSC models derived from patients with neurodegenerative disorders. These datasets could be exploited for biomarker prediction in neurodegenerative disorders. Dive into Polly's bulk RNA-seq datasets to gain deeper insights into the genetic underpinnings of various traits and conditions, ultimately advancing the possibilities in biomarker predictions and drug discovery.
Transcriptomics analysis of human iPSC-derived dopaminergic neurons reveals a novel model for sporadic Parkinson's disease.
Dataset ID: GSE196190_GPL24676_raw
Year of Publication: 2022
Experiment Type: Bulk RNA-seq
Total Samples: 24
Organism: Homo sapiens
Reference Link: Publication
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 1% of the population aged 65 and older. While some PD cases have a genetic basis, the majority occur sporadically. Risk factors include not only genetics, age, and gender but also exposure to neurotoxic substances such as pesticides and herbicides. Since PD is characterized by the loss of dopaminergic neurons in the substantia nigra, it is challenging to access and extract these cells from patients to study the disease's mechanisms.
The emergence of iPSC technology offers a solution by allowing the differentiation and cultivation of human dopaminergic neurons. These iPSC-derived neurons serve as a valuable tool for in vitro disease modeling. In a recent study, researchers differentiated human iPSCs into dopaminergic neurons and exposed them to increasing concentrations of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). They observed a strong, time- and dose-dependent response through temporal transcriptomics analysis. Many genes associated with PD etiology were overrepresented across pathways such as "Parkinson's Disease," "Dopaminergic Signaling," and "Calcium Signaling." Furthermore, scientists validated this disease model by demonstrating a robust overlap with a meta-analysis of transcriptomics data obtained from post-mortem PD patients' substantia nigra. The shared genes were linked to mitochondrial dysfunction, neuron differentiation, apoptosis, and inflammation.
The data suggests that MPP+-induced human iPSC-derived dopaminergic neurons exhibit molecular perturbations consistent with the pathogenesis of PD. This study proposes iPSC-derived dopaminergic neurons as a foundation for a novel sporadic PD model, providing insights into the disease's pathomolecular mechanisms and enabling the screening of potential anti-PD drugs.
To demonstrate how Polly can enhance your data visualization, we selected the top 10 genes associated with PD, and the bar graphs illustrate the most enriched pathways related to PD in Reactome, KEGG, GOBP, and GWAS.
Reactive human iPSC astrocytes suppress oligodendrocyte precursor cell differentiation.
Dataset ID: GSE196575_GPL24676_raw
Year of Publication: 2022
Experiment Type: Bulk RNA-seq
Total Samples: 43
Organism: Homo sapiens
Reference Link: Publication
Astrocytes are crucial in maintaining central nervous system homeostasis and responding to tissue injuries. While astrocyte activation can be a beneficial response to acute pathologies, prolonged reactive gliosis is believed to be injurious in neurodegenerative diseases, including multiple sclerosis (MS). One significant limitation in studying neurodegenerative diseases is the scarcity of human pathological specimens obtained during the acute stages, which often confines research to post-mortem specimens collected years after the initiation of pathology.
Reactive astrocytes in rodents are cytotoxic to neurons and oligodendrocytes, but there may be differences in human cells, particularly in diseases with known genetic susceptibility. In this study, the authors isolated human CD49f+ astrocytes from differentiated iPSCs derived from individual patients and controlled peripheral white blood cell samples. They compared TNF and IL1α-stimulated human reactive astrocytes from seven individuals with MS and six non-MS controls, revealing that their specific astrocyte transcriptomic profiles closely resemble those described in rodents. The functional impact of astrocyte-conditioned media (ACM) was assessed using a human oligodendrocyte precursor cell (OPC) line differentiation assay with a transgenic secreted reporter of myelin basic protein (MBP) expression. ACM did not prove cytotoxic to the OPCs but significantly inhibited the MBP reporter.
No differences were observed between MS and control-stimulated astrocytes at either the transcript level or functional OPC suppression assays. The authors then employed RNA-seq to investigate differentially expressed genes in the OPC lines that had their differentiation suppressed by the human ACM. Remarkably, not only was OPC differentiation and myelin gene expression inhibited, but the induction of several immune pathways and Nf-κB signaling in OPCs exposed to the ACM was also observed. These findings support the idea that reactive astrocytes can impede OPC differentiation, thereby limiting their remyelination capacity and that OPCs adopt an immune profile in the context of inflammatory cues.
The first step in discovering biomarkers is to identify differentially expressed genes in the control and patient groups. Here, we performed differential gene expression analysis on harmonized and normalized data of MS and control. The heatmap illustrates genes that exhibit significant differential expression, meeting the criteria of Log Fold Change (Log FC) >= |1| and a p-value of <= 0.01.
Enhanced deoxysphingobase production in HSN1 results in sensory nerve toxicity through deficits in both cell-autonomous and axoglial signaling, ameliorated by serine treatment.
Dataset ID: GSE144208_GPL20301_raw
Year of Publication: 2020
Experiment Type: Bulk RNA-seq
Total Samples: 35
Organism: Homo sapiens
Reference Link: Publication
An iPSC model of hereditary sensory neuropathy-1 (HSN1) reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions. HSN1 is caused by mutations in the SPTLC1 or SPTLC2 subunits of the enzyme serine palmitoyltransferase, resulting in the production of toxic 1-deoxysphingolipid bases (DSBs). The authors used induced pluripotent stem cells (iPSCs) from patients with HSN1 to investigate the neurotoxicity of endogenous DSBs, pathomechanisms of toxicity, and therapeutic response. HSN1 iPSC-derived sensory neurons naturally produce neurotoxic DSBs.
Complex gangliosides, crucial for membrane microdomains and signaling, are reduced, impairing neurotrophin signaling and diminished neurite outgrowth. In HSN1 myelinating cocultures, the researchers observed significant disruption of nodal complex proteins after eight weeks, ultimately resulting in complete myelin breakdown after six months. HSN1 iPSC models have revealed that SPTLC1 mutation alters lipid metabolism, impairs complex ganglioside formation, and reduces axon and myelin stability. Importantly, many of these changes can be prevented by l-serine supplementation, supporting its use as a rational therapy.
The volcano plot illustrates the genes that are significantly expressed in patients with HSN1 and normal control.
Impairment of mitochondrial calcium buffering links mutations in C9orf72 and TARDBP in iPS-derived motor neurons from patients with ALS/FTD.
Dataset ID: GSE147544_GPL20301_raw
Year of Publication: 2020
Experiment Type: Bulk RNA-seq
Total Samples: 10
Organism: Homo sapiens
Reference Link: Publication
TDP-43 dysfunction is common in 97% of amyotrophic lateral sclerosis (ALS) cases, including those with C9ORF72 mutations. To investigate how C9ORF72 mutations drive cellular pathology in ALS and to identify convergent mechanisms shared between C9ORF72 and TARDBP mutations, researchers analyzed motor neurons (MNs) derived from iPSCs of ALS patients. C9ORF72 iPSC-MNs exhibit increased Ca2+ release after depolarization, delayed recovery to baseline following glutamate stimulation, and lower levels of calbindin compared to CRISPR/Cas9 genome-edited controls.
TARDBP iPSC-derived MNs display high glutamate-induced Ca2+ release. RNA sequencing reveals that C9ORF72 and TARDBP iPSC-MNs upregulate Ca2+-permeable AMPA and NMDA subunits. Additionally, there's an impairment of mitochondrial Ca2+ buffering due to an imbalance of MICU1 and MICU2 on the mitochondrial Ca2+ uniporter. This indicates that impaired mitochondrial Ca2+ uptake contributes to glutamate excitotoxicity, serving as a shared feature of MNs with C9ORF72 or TARDBP mutations.
The first step in biomarker discovery is identifying differentially expressed genes in the control and patient groups. We performed differential gene expression analysis on harmonized and normalized ALS and control data. The heatmap displays genes with significant differential expression (condition Log FC >= |1| & P-value <= 0.01).
Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome.
Dataset ID: GSE126359_GPL18573_raw
Year of Publication: 2021
Experiment Type: Bulk RNA-seq
Total Samples: 12
Organism: Homo sapiens
Reference Link: Publication
Leigh syndrome (LS) is a severe childhood manifestation of mitochondrial disease with no cure. The lack of effective models has hindered our understanding of the mechanisms behind LS neuronal pathology. The authors developed a human LS model to address this gap using patient-derived iPSCs and CRISPR/Cas9 engineering. This model simulates LS caused by mutations in the complex IV assembly gene SURF1. Through single-cell RNA-sequencing and multi-omics analysis, they uncovered compromised neuronal morphogenesis in mutant neural cultures and brain organoids.
The defects were traced back to the neural progenitor cells (NPCs) level, which remained in a glycolytic proliferative state, failing to trigger neuronal morphogenesis. When LS NPCs with mutations in the complex I gene NDUFS4 were examined, they displayed similar morphogenesis defects. To address these issues, the researchers augmented the SURF1 gene and induced PGC1A via bezafibrate treatment, successfully restoring neuronal morphogenesis. These findings offer valuable mechanistic insights and suggest potential interventional strategies for this rare mitochondrial disease.
We performed PCA on the differentially expressed genes of both patient-derived and control iPSCs. This analysis demonstrates distinct clusters formed by these cells based on their classification.
Deciphering the secrets of disease origins empowers us with valuable insights into disease progression and the ability to predict crucial biomarkers. This is made possible by identifying differentially expressed genes at distinct disease stages—a game-changer in the healthcare and diagnostics landscape. Polly isn't just a game-changer; it's your gateway to Polly-verified high-quality data and results. By seamlessly integrating critical metadata aligned with your research, Polly elevates data integrity through uniform processing and comprehensive annotation. Its adaptable harmonization engine is ready to scale for your needs, whether tailored metadata, diverse data types, or specific cohorts, to foster precision.
Ready to accelerate your research journey? Connect with us to discuss how Polly can potentially reduce your analysis time by up to 80% in gene and pathway analysis to expedite the drug discovery process.
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