Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations

Translational Psychiatry, Journal Year: 2023, Volume and Issue: 13(1)

Published: July 6, 2023

Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal repetitive behavior patterns. Over hundreds of genes thousands genetic variants were reported to be highly penetrant causative ASD. Many these mutations cause comorbidities such as epilepsy intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) patients with four in the GRIN2B, SHANK3, UBTF, well chromosomal duplication 7q11.23 region compared them a first-degree relative without mutation. Using whole-cell patch-clamp, observed that mutant demonstrated hyperexcitability early maturation control lines. These changes increased sodium currents, amplitude rate excitatory postsynaptic currents (EPSCs), more evoked action potentials response current stimulation early-stage cell development (3-5 weeks post differentiation). appeared all different lines, together previously data, indicate an may convergent phenotype ASD neurons.

Language: Английский

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Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 19, 2024

Parkinson's disease (PD) is a neurodegenerative with both genetic and sporadic origins. In this study, we investigated the electrophysiological properties, synaptic activity, gene expression differences in dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSCs) of healthy controls, PD (sPD) patients, patients E326K-GBA1 mutations. Our results demonstrate reduced sodium currents activity DA mutations, suggesting potential contribution to pathophysiology. We also observed distinct alterations sPD neurons, which included decrease currents. RNA sequencing analysis revealed unique dysregulated pathways further supporting notion that molecular mechanisms driving may differ between patients. agreement our previous reports, Extracellular matrix Focal adhesion were among top Overall, study confirms impaired convergent functional phenotype across multiple mutations as well sPD. At transcriptome level, find brain extracellular highly involved pathology PD-associated

Language: Английский

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Gene Expression Profiling of Post Mortem Midbrain of Parkinson’s Disease Patients and Healthy Controls

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 707 - 707

Published: Jan. 5, 2024

Parkinson's disease (PD) stands as the most prevalent degenerative movement disorder, marked by degeneration of dopaminergic neurons in substantia nigra midbrain. In this study, we conducted a transcriptome analysis utilizing post mortem mRNA extracted from both PD patients and healthy control (CTRL) individuals. Specifically, acquired eight samples individuals with six CTRL individuals, no discernible pathology detected latter group. RNA sequencing was using TapeStation 4200 system Agilent Technologies. A total 16,148 transcripts were identified, 92 mRNAs displaying differential expression between groups. 33 significantly up-regulated, while 59 down-regulated compared to controls. The identification statistically significant signaling pathways, an adjusted p-value threshold 0.05, unveiled noteworthy insights. enriched categories included cardiac muscle contraction (involving genes such ATPase Na+/K+ transporting subunit beta 2 (ATP1B2), solute carrier family 8 member A1 (SLC8A1), cytochrome c oxidase II (COX2)), GABAergic synapse GABA type receptor-associated protein-like 1 (GABARAPL1), G protein 5 (GNB5), 38 (SLC38A2), autophagy GABARAPL1 tumor p53-inducible nuclear (TP53INP2)), Fc gamma receptor (FcγR) mediated phagocytosis amphiphysin (AMPH)). These findings uncover new pathophysiological dimensions underlying PD, implicating associated heart contraction. This knowledge enhances diagnostic accuracy contributes advancement targeted therapies.

Language: Английский

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Differential gene expression patterns in Niemann-Pick Type C and Tay-Sachs diseases: Implications for neurodegenerative mechanisms

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(3), P. e0319401 - e0319401

Published: March 19, 2025

Lysosomal storage disorders (LSDs) are a group of rare genetic conditions characterized by the impaired function enzymes responsible for lipid digestion. Among these LSDs, Tay-Sachs disease (TSD) and Niemann-Pick type C (NPC) may share common gene expression profile. In this study, we conducted bioinformatics analysis to explore profile overlap between TSD NPC. Analyses were performed on RNA-seq datasets both NPC from Gene Expression Omnibus (GEO) database. Datasets subjected differential utilizing DESeq2 package in R programming language. A total 147 differentially expressed genes (DEG) found be shared datasets. Enrichment was then DEGs. We that DEGs predominantly associated with processes such as cell adhesion mediated integrin, cell-substrate adhesion, urogenital system development. Furthermore, construction protein-protein interaction (PPI) networks using Cytoscape software led identification four hub genes: APOE , CD44 SNCA ITGB5 . Those not only can unravel pathogenesis related neurologic diseases pathways, but also pave way towards targeted therapy LSDs.In addition, they serve potential biomarkers neurodegenerative warranting further investigations.

Language: Английский

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Multifaceted collagen-DDR1 signaling in cancer

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 34(5), P. 406 - 415

Published: Sept. 12, 2023

Language: Английский

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Integrated bioinformatics analysis for exploring potential biomarkers related to Parkinson’s disease progression

BMC Medical Genomics, Journal Year: 2024, Volume and Issue: 17(1)

Published: May 17, 2024

Abstract Background Parkinson’s disease (PD) is a progressive neurodegenerative with increasing prevalence. Effective diagnostic markers and therapeutic methods are still lacking. Exploring key molecular mechanisms for PD can help early diagnosis treatment improvement. Methods Three datasets GSE174052, GSE77668, GSE168496 were obtained from the GEO database to search differentially expressed circRNA (DECs), miRNAs (DEMis), mRNAs (DEMs). GO KEGG enrichment analyses, protein–protein interaction (PPI) network construction implemented explore possible actions of DEMs. Hub genes selected establish circRNA-related competing endogenous RNA (ceRNA) networks. Results There 1005 downregulated DECs, 21 upregulated DEMis, 266 234 DEMs identified. The significantly enriched in various PD-associated functions pathways such as extracellular matrix organization, dopamine synthesis, PI3K-Akt, calcium signaling pathways. Twenty-one hub screened out, PD-related ceRNA regulatory was constructed containing 31 circRNAs, one miRNA (miR-371a-3p), gene ( KCNJ6 ). Conclusion We identified networks, providing new directions treatment.

Language: Английский

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A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson’s Disease

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(6), P. 522 - 522

Published: May 21, 2024

The role of the extracellular matrix (ECM) in Parkinson's disease (PD) is not well understood, even though it critical for neuronal structure and signaling. This systematic review identified top deregulated ECM-related pathways studies that used gene set enrichment analyses (GSEA) to document transcriptomic, proteomic, or genomic alterations PD. PubMed Google scholar were searched transcriptomics, proteomics, genomics employed GSEA on data from PD tissues cells reported among top-10 most enriched versus controls. Twenty-seven included, two which multiple omics analyses. Transcriptomics proteomics conducted a variety tissue cell types. Of 17 transcriptomics (16 sets), 13 one more adhesion sets pathways, primarily related focal adhesion. Among 8 studies, 5 altered overarching ECM 10. 4 3 findings summarized here suggest organization/structure (particularly adhesion) are should be focus future studies.

Language: Английский

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Astrocyte‐derived factors regulate CNS myelination

Glia, Journal Year: 2024, Volume and Issue: 72(11), P. 2038 - 2060

Published: Aug. 2, 2024

Abstract The role that astrocytes play in central nervous system (CNS) myelination is poorly understood. We investigated the contribution of astrocyte‐derived factors to and revealed a substantial overlap secretomes human rat astrocytes. Using vitro myelinating co‐cultures primary retinal ganglion cells cortical oligodendrocyte precursor cells, we discovered secreted by resting astrocytes, but not reactive facilitated myelination. Soluble brevican emerged as new enhancer developmental vivo, CNS its absence was linked remyelination deficits following an immune‐mediated damage EAE mouse model. observed reduction expression MS lesions suggested potential link compromised characteristic neurodegenerative diseases. Our findings brevican's may be mediated through interactions with binding partners such contactin‐1 tenascin‐R. Proteomic analysis versus highlighted shift protein profiles, pinpointing candidates either facilitate or impede repair, suggesting depending on their reactivity state, dual during

Language: Английский

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Focusing on the tetra-partite synapse in Parkinson’s disease research using human patient-derived neurons

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 19(5), P. 979 - 981

Published: Aug. 14, 2023

Parkinson's disease (PD) was first described as a neurological by Dr. James Parkinson in 1817 "shaking palsy". Since that time, much more is known about the pathophysiology of PD yet still uncurable. The hallmark often considered Lewy body neural inclusions substantia nigra pars compacta and other brain areas, although not all patients have these inclusions. exhibit massive neuronal cell loss compacta, which associated with motor symptoms tremor, bradykinesia, rigidity, postural instability. second most common neurodegenerative after Alzheimer's prevalence around 1% individuals over age 60. progressive incurable non-motor symptoms, sometimes prodromal, such depression, impaired olfaction, constipation, urinary dysfunction, decreased respiratory muscle strength, more. Animal vivo models been widely used to study PD. However, their limitations include species differences inability fully replicate human disease, especially sporadic forms disease. Human induced pluripotent stem cells (iPSCs) offer potential generate patient-specific neurons can recapitulate disease-specific phenotypes. This approach enabled discovery some pathophysiological mechanisms, gene dysregulation, affected pathways, electrophysiological neurodevelopmental, neuropsychiatric, disorders (Schafer et al., 2019; Stern 2023). In last decade, several mutations discovered associate even cause PD, account for 15–25% cases, while rest are (sPD). Using derived from iPSC technologies revealed new mechanistic understandings pathological processes (Lau 2021; 2022b, c, 2023; van den Hurk 2022; Rike Stern, Rosh These studies measured changes electrophysiology, transcriptome, metabolome dopaminergic (DA) quite few monogenic well sPD. novel cellular allowed identification mutation-specific neurophysiology, importantly convergent biological mechanisms harbor variety but similar symptoms. recent paper (Stern 2022b), significant reduction synaptic activity observed DA duplication triplication synuclein alpha (SNCA), leucine-rich repeat kinase 2 (LRRK2), Parkin mutations, sPD patients. sPD-related phenotypes were milder. Figure 1 shows deficits reported al. (2022b) through recordings using whole-cell patch-clamp differentiated reported. reports highlight emphasize deficit hypothesis previously suggested small number mice models.Figure 1: A rate excitatory post-synaptic currents (EPSCs) across (sPD).The images presented further analysis cohort (2022b). (A) EPSCs recorded healthy control, alpha-synuclein (SNCA) triplication, specific mutation SNCA gene, where amino acid alanine replaced threonine at position 5 (SNCA-A53T), (LRRK2) mutation, duplication, glucocerebrosidase (GBA) PARK2 responsible encoding parkin protein (Parkin mutation) Created Adobe illustrator. (B) decrease Dopaminergic synapse (left panel) created BioRender.com. (C) Representative traces evoked action potentials controls show no excitability. Unpublished data.The conducted unknown genes convergently differentially expressed lines form including many collagens integrin genes. confirmed protein-level experiments. Additionally, ontology pathway analysis, pathways appeared be focal adhesion, PI3K-Akt signaling, extracellular matrix (ECM)-related related cancer, oxidoreductase activity, digestion absorption. addition synapse-related synapse, membrane, post-synapse. findings extremely important since years focus has put on contribution progression. Recently, roles glial also recognized. role glia complex they being elucidated years. Astrocytes microglia involved neuroinflammatory response caused accumulation α-synuclein damage, astrocytes contribute mitochondrial dysfunction oxidative stress, oligodendrocytes myelin disruption axonal degeneration (Araújo 2022). little effort directed toward studying environment 2022b; 2023) suggest ECM adhesion (the pathways) dysregulated three-dimensional network water, proteins, polysaccharides. provides physical scaffold facilitates organization into distinct central nervous system regions. During development, it produces diverse molecular signals guide growth regulating morphogenesis developing tube neocortex, impacting tissue. implicated neurogenesis, migration differentiation, pathfinding (Myers 2011). adult system, maintaining homeostasis remodeling plasticity (Ferrer-Ferrer Dityatev, 2018). contains three main structural components: basement perineuronal nets, interstitial matrix. connections recently recognized now part tetrapartite consisting pre-synaptic neurons, glia, (Dityatev Rusakov, Accumulating data support interactions between presynaptic postsynaptic elements formation chemical synapses Neural formed destroyed an activity-dependent manner. lattices tightly enwrap synapses. stabilize synapses, preventing them undergoing or morphological changes. need permit events plasticity. dysregulation linked synaptopathies long list aberrant appears iPSC-derived same time maybe therefore one another. Mice shown present already when young stage, express lower level than subjects Focal integrins down-regulated this stage. defective may neurodegeneration mechanisms. One termed Anoikis – death detachment ECM. presents adhesion-related re-analyzing (2022b).Figure 2: Common (sPD) (ECM) pathways.The graphs re-analysis RNA sequencing our 2022b). receptor interaction: 9 7 common. organization: 16 14 sPD, 11 constituent: (D) ECM: 15 differently monogenic, 10 (E) adhesion: 21 (F) 13 illustrator.Through sequencing, shared types signaling pathways. It plays crucial wide range processes, growth, survival, proliferation, metabolism, synthesis. Activation promotes survival stimulating synthesis, inhibiting apoptosis, promoting cycle Dysregulation pathogenesis diseases, diabetes, diseases More transcriptome published looking differential expression signatures midbrain (van They analyzed 80 bulk RNA-seq samples, 5315 single-cell RNA-sequencing 44 Patch-seq samples. researchers combined transcriptomes familial genotypes. research identified six major disrupted neurotransmission function, energy neuromorphogenesis & cytoskeleton (including intracellular trafficking, inflammation immunity, stress responses. development technology iPSCs, bio-engineered tissues unique experimental opportunity uncover dysregulations precede humans. reinforce future therapeutic pipelines, will required assess pharmacological rescue multiple transcriptomic neurons. Importantly, another unexplored mechanism relates space. Together analyses, provide evidence tetra-partite neuron, highly following review aimed summarize ECM-related postmortem tissue explored literature focused transcriptional proteomic occur during (Rike collagens, integrins, annexins, tenascins, versicans commonly proteins frontal cortex collagen both iPSCs studies. IV VI versican, interact impact survival. addition, proteases regulator enzymes metalloproteinases disintegrin metalloproteases model severely Interestingly, well. Just example, we note relating adhesions top bipolar disorder (Santos 2021), autism (Brant schizophrenia 2022a). disorders, analyzing electrophysiology. 3D organoid (Steinberg 2021). When aiming involvement, how affects neurodegeneration, 2D structures scaffolds. Switching organoids necessary. brain-like enable dynamic measurement localizations aggregations space various process brain. production, embryoid bodies embedded Matrigel. Matrigel available enriched laminin. generation disruptive trying calls added embeddings. Such gels today sources synthetic-matrix-based should developed before continue summary, excellent investigate Several ECM, play pathophysiology, putting area rather itself. dopamine precursors, delivering possibilities. Although use very promising field, there different recapitulated. As discussed, currently suitable work synthetic gel-based proceeding. On hand, perspectives exciting because possibilities For instance, personalized medicine thanks ability drug responses each patient, could lead treatment options advances gene-editing made possible introduce correct patient-derived helping pinpoint causative neurodegeneration. Overall, holds great promise advancing understanding treatments. supported Israel Science Foundation (ISF grant 1994/21 3252/21) Zuckerman (Zuckerman STEM leadership program) (to SS). C-Editors: Zhao M, Sun Y, Qiu Y; T-Editor: Jia Y

Language: Английский

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Leveraging Biomaterial Platforms to Study Aging-Related Neural and Muscular Degeneration

Biomolecules, Journal Year: 2024, Volume and Issue: 14(1), P. 69 - 69

Published: Jan. 4, 2024

Aging is a complex multifactorial process that results in tissue function impairment across the whole organism. One of common consequences this loss muscle mass and associated decline function, known as sarcopenia. also presents with an increased risk developing other pathological conditions such neurodegeneration. Muscular neuronal degeneration cause mobility issues cognitive impairment, hence having major impact on quality life older population. The development novel therapies can ameliorate effects aging currently hindered by our limited knowledge underlying mechanisms use models fail to recapitulate structure composition cell microenvironment. emergence bioengineering techniques based biomimetic materials biofabrication methods has opened possibility generating 3D muscular nervous tissues better mimic native extracellular matrix. These platforms are particularly advantageous for drug testing mechanistic studies. In review, we discuss developments made creation aging-related provide perspective future directions field.

Language: Английский

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