Oligonucleotides Targeting DNA Repeats Downregulate Gene Expression in Huntington's Patient-Derived Neural Model System.

Huntington's disease (HD) is one of the most common, dominantly inherited neurodegenerative disorders. It affects the striatum, cerebral cortex, and other subcortical structures leading to involuntary movement abnormalities, emotional disturbances, and cognitive impairments. HD is caused by a CAG•CTG trinucleotide-repeat expansion in exon 1 of the () gene leading to the formation of mutant HTT (mtHTT) protein aggregates.

TGF-β1 Suppresses Proliferation and Induces Differentiation in Human iPSC Neural Models.

Persistent neural stem cell (NSC) proliferation is, among others, a hallmark of immaturity in human induced pluripotent stem cell (hiPSC)-based neural models. TGF-β1 is known to regulate NSCs during embryonic development in rodents. Here we examined the role of TGF-β1 as a potential candidate to promote differentiation of hiPSCs-derived NSCs and maturation of neuronal progenies.

Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder.

Identification of causative genetic variants leading to the development of bipolar disorder (BD) could result in genetic tests that would facilitate diagnosis. A better understanding of affected genes and pathways is also necessary for targeting of genes that may improve treatment strategies. To date several susceptibility genes have been reported from genome-wide association studies (GWAS), but little is known about specific variants that affect disease development.

Tumorigenic effects of TLX overexpression in HEK 293T cells.

Background: The human orphan receptor TLX (NR2E1) is a key regulator of neurogenesis, adult stem cell maintenance, and tumorigenesis. However, little is known about the genetic and transcriptomic events that occur following TLX overexpression in human cell lines.

Aims: Here, we used cytogenetics and RNA sequencing to investigate the effect of TLX overexpression with an inducible vector system in the HEK 293T cell line.

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma.

(1) Background: BET bromodomain proteins regulate transcription by binding acetylated histones and attracting key factors for, e.g., transcriptional elongation.

Author Correction: Accelerated neuronal and synaptic maturation by BrainPhys medium increases Aβ secretion and alters Aβ peptide ratios from iPSC-derived cortical neurons.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Accelerated neuronal and synaptic maturation by BrainPhys medium increases Aβ secretion and alters Aβ peptide ratios from iPSC-derived cortical neurons.

One of the neuropathological hallmarks of Alzheimer's disease (AD) is cerebral deposition of amyloid plaques composed of amyloid β (Aβ) peptides and the cerebrospinal fluid concentrations of those peptides are used as a biomarker for AD. Mature induced pluripotent stem cell (iPSC)-derived cortical neurons secrete Aβ peptides in ratios comparable to those secreted to cerebrospinal fluid in human, however the protocol to achieve mature neurons is time consuming. In this study, we investigated if differentiation of neuroprogenitor cells (NPCs) in BrainPhys medium, previously reported to enhance synaptic function of neurons in culture, would accelerate neuronal maturation and, thus increase Aβ secretion as compared to the conventional neural maintenance medium.

Robust Generation of Person-Specific, Synchronously Active Neuronal Networks Using Purely Isogenic Human iPSC-3D Neural Aggregate Cultures.

Reproducibly generating human induced pluripotent stem cell-based functional neuronal circuits, solely obtained from single individuals, poses particular challenges to achieve personalized and patient specific functional neuronal models. A hallmark of functional neuronal assemblies, synchronous neuronal activity, can be non-invasively studied by microelectrode array (MEA) technology, reliably capturing physiological and pathophysiological aspects of human brain function. In our here presented manuscript, we demonstrate a procedure to generate 3D neural aggregates comprising astrocytes, oligodendroglial cells, and neurons obtained from the same human tissue sample.

Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages.

Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls).

Comparison of the glycosphingolipids of human-induced pluripotent stem cells and human embryonic stem cells.

High expectations are held for human-induced pluripotent stem cells (hiPSC) since they are established from autologous tissues thus overcoming the risk of allogeneic immune rejection when used in regenerative medicine. However, little is known regarding the cell-surface carbohydrate antigen profile of hiPSC compared with human embryonic stem cells (hESC). Here, glycosphingolipids were isolated from an adipocyte-derived hiPSC line, and hiPSC and hESC glycosphingolipids were compared by concurrent characterization by binding assays with carbohydrate-recognizing ligands and mass spectrometry.

TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.

Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity.

Calcium-dependent intracellular signal pathways in primary cultured adipocytes and ANK3 gene variation in patients with bipolar disorder and healthy controls.

Bipolar disorder (BD) is a chronic psychiatric disorder of public health importance affecting >1% of the Swedish population. Despite progress, patients still suffer from chronic mood switches with potential severe consequences. Thus, early detection, diagnosis and initiation of correct treatment are critical.

SAF-A forms a complex with BRG1 and both components are required for RNA polymerase II mediated transcription.

Background: Scaffold attachment factor A (SAF-A) participates in the regulation of gene expression by organizing chromatin into transcriptionally active domains and by interacting directly with RNA polymerase II.

Methodology: Here we use co-localization, co-immunoprecipitation (co-IP) and in situ proximity ligation assay (PLA) to identify Brahma Related Gene 1 (BRG1), the ATP-driven motor of the human SWI-SNF chromatin remodeling complex, as another SAF-A interaction partner in mouse embryonic stem (mES) cells. We also employ RNA interference to investigate functional aspects of the SAF-A/BRG1 interaction.

SAF-A has a role in transcriptional regulation of Oct4 in ES cells through promoter binding.

Methodologies to reprogram somatic cells into patient-specific pluripotent cells, which could potentially be used in personalized drug discovery and cell replacement therapies, are currently under development. Oct4 activation is essential for successful reprogramming and pluripotency of embryonic stem (ES) cells, albeit molecular details of Oct4 activation are not completely understood. Here we report that endogenous SAF-A is involved in regulation of Oct4 expression, binds the Oct4 proximal promoter in ES cells, and dissociates from the promoter upon early differentiation induced by LIF withdrawal.

Translationally controlled tumor protein interacts with nucleophosmin during mitosis in ES cells.

Somatic cell nuclear transfers and the generation of induced pluripotent stem cells provide potential routes towards non-immunogenic cell replacement therapies. Translationally controlled tumor protein (Tpt1) was recently suggested to regulate cellular pluripotency. Here we explore functions of Tpt1 in mouse embryonic stem (ES) cells.

Developmental studies of Xenopus shelterin complexes: the message to reset telomere length is already present in the egg.

The 6-protein complex shelterin protects the telomeres of human chromosomes. The recent discovery that telomeres are important for epigenetic gene regulation and vertebrate embryonic development calls for the establishment of model organisms to study shelterin and telomere function under normal developmental conditions. Here, we report the sequences of the shelterin-encoding genes in Xenopus laevis and its close relation Xenopus tropicalis.