Neural Cell News Volume 13.42 | Oct 30 2019

TOP STORY

Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

The authors generated human induced pluripotent stem cells from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulated key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. [Nat Commun] Full Article

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Two Adhesive Systems Cooperatively Regulate Axon Ensheathment and Myelin Growth in the CNS

Using combined morphological and molecular analyses in mice and zebrafish, investigators showed that adhesion molecules of the paranodal and the internodal segment worked synergistically using overlapping functions to regulate axonal interaction and myelin wrapping. In the absence of these adhesive systems, axonal recognition by myelin was impaired with myelin growing on top of previously myelinated fibers, around neuronal cell bodies and above nodes of Ranvier. [Nat Commun] Full Article

CRH Promotes the Neurogenic Activity of Neural Stem Cells in the Adult Hippocampus

Scientists showed that corticotropin-releasing hormone (CRH), the major mediator of mammalian stress response and a key neuromodulator in the adult brain, was necessary for hippocampal neural stem cell (hiNSC) activity under physiological conditions. They demonstrated functionality of the CRH/CRH receptor system in mouse hiNSCs and conserved expression in humans. [Cell Rep] Full Article | Graphical Abstract

Oligodendrocyte Intrinsic miR-27a Controls Myelination and Remyelination

Increased levels of miR-27a led to inhibition of oligodendrocyte progenitor cells (OPC) proliferation by cell-cycle arrest, as well as impaired differentiation of human OPCs and myelination by dysregulating the Wnt-β-catenin signaling pathway. In vivo administration of miR-27a led to suppression of myelinogenic signals, leading to loss of endogenous myelination and remyelination. [Cell Rep] Full Article | Graphical Abstraction

Development of an AAV-Based microRNA Gene Therapy to Treat Machado-Joseph Disease

miATXN3 candidates were screened in vitro based on their silencing efficacy on a luciferase reporter co-expressing ATXN3. The three best miATXN3 candidates were further tested for target engagement and potential off-target activity in induced-pluripotent stem cells differentiated into frontal brain-like neurons and in a SCA3 knock-in mouse model. [Mol Ther Methods Clin Dev] Abstract

IRE1 Promotes Neurodegeneration yhrough Autophagy-Dependent Neuron Death in the Drosophila Model of Parkinson’s Disease

Researchers found that inositol-requiring enzyme 1 (IRE1) was hyperactivated upon accumulation of α-synuclein in the fly photoreceptor neurons. Ectopic overexpression of IRE1 was sufficient to trigger autophagy-dependent neuron death in an XBP1-independent, JNK-dependent manner. [Cell Death Dis] Full Article

Ionizing Radiation Induces Endothelial Transdifferentiation of Glioblastoma Stem-Like Cells through the Tie2 Signaling Pathway

Glioblastoma stem cell (GSC) neurospheres isolated from three different patients were irradiated or not and were then transdifferentiated into tumor derived endothelial cells (TDEC). TDEC obtained from irradiated GSC migrated more towards VEGF, formed more pseudotubes in Matrigel™ in vitro and developed more functional blood vessels in Matrigel&tm; plugs implanted in nude mice than TDEC obtained from non-irradiated GSC. [Cell Death Dis] Full Article

LXRβ Controls Glioblastoma Cell Growth, Lipid Balance, and Immune Modulation Independently of ABCA1

Scientists showed that high cell density induced ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), they investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. [Sci Rep] Full Article

Modeling Monogenic Autism Spectrum Disorder Using Mouse Cortical Organoids

Researchers studied mouse cortical organoids derived from Cntnap2^−/− (KO) mouse induced pluripotent stem cells. Their results showed that KO mouse cortical organoids displayed inhibitory-neuron-specific defects. At the neural progenitor stage, the GABAergic-neurogenesis-governing transcriptional network was dysregulated in the absence of Cntnap2. [Biochem Biophys Res Commun] Abstract

FRET-Based Cyclic GMP Biosensors Measure Low cGMP Concentrations in Cardiomyocytes and Neurons

Investigators developed a fluorescence resonance energy transfer (FRET)-based cGMP biosensor with high affinity for cGMP as a tool for intracellular signaling studies. They used the carboxyl-terminal cyclic nucleotide binding domain of Plasmodium falciparum cGMP-dependent protein kinase flanked by different FRET pairs to generate two cGMP biosensors. [Commun Biol] Full Article

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Cellular Models of Batten Disease

The authors review how cell models have informed much of the biochemical understanding of the neuronal ceroid lipofuscinoses and how more complex models are being used to further this understanding and potentially act as platforms for therapeutic efficacy studies in the future. [BBA-Mol Basis Dis] Full Article | Graphical Abstract

Role of GPCR Signaling and Calcium Dysregulation in Alzheimer’s Disease

Investigators summarize the different calcium channels and receptors involved in calcium dysregulation which in turn play a critical role in the pathogenesis of Alzheimer’s disease (AD). Understanding the role of calcium channels and GPCRs to maintain calcium homeostasis is an attempt to develop effective AD treatments. [Mol Cell Neurosci] Abstract

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Mapi Announces First Patient Enrolled in the Phase III Clinical Trial of GA Depot for Relapsing Multiple Sclerosis (RMS)

Mapi Pharma Ltd. announced that the first patient has been enrolled in its Phase III study with GA Depot for relapsing forms of MS. Glatiramer acetate, the active material of Copaxone^®, or its generic forms, is the most common treatment for RMS in the US. GA Depot is a long0acting depot formulation injection of glatiramer acetate administered once every four weeks, compared with the daily or thrice weekly regimen used with Copaxone^® or its generic forms. [Mapi Pharma Ltd.] Press Release

Galimedix Therapeutics, Inc.’s GAL-101 Gains From Target Validation by Positive Phase III Results of Biogen’s Aducanumab

Galimedix Therapeutics, Inc. announced that the recent positive results of a Phase III study in Alzheimer’s disease with Biogen’s aducanumab also validate the target of the company’s lead molecule, GAL-101. [Galimedix Therapeutics, Inc.] Press Release

Mustang Bio Announces Dosing of First Participant in Phase I Clinical Trial of MB-108 (Oncolytic Virus C134) to Treat Glioblastoma

Mustang Bio, Inc. announced that the first participant has been dosed in a Phase I clinical trial to determine the safety and efficacy of MB-108, an attenuated herpes simplex virus type 1, in recurrent glioblastoma multiforme. [Mustang Bio, Inc.] Press Release

NurOwn^® Data Safety Monitoring Board Recommends ALS Phase III Clinical Trial Continue

BrainStorm Cell Therapeutics, Inc. announced that the Phase III clinical trial independent Data Safety Monitoring Board has completed the second, pre-specified interim analysis, of safety outcomes for the first 106 patients who received repeat dosing of NurOwn^® in the Phase III trial for ALS patients. [BrainStorm Cell Therapeutics, Inc.] Press Release

Biogen Plans Regulatory Filing for Aducanumab in Alzheimer’s Disease Based on New Analysis of Larger Dataset From Phase III Studies

Biogen and Eisai, Co., Ltd. announced that, after consulting with the FDA, Biogen plans to pursue regulatory approval for aducanumab, an investigational treatment for early Alzheimer’s disease. The Phase III EMERGE Study met its primary endpoint showing a significant reduction in clinical decline, and Biogen believes that results from a subset of patients in the Phase III ENGAGE Study who received sufficient exposure to high dose aducanumab support the findings from EMERGE. [Biogen] Press Release | Editorial

California Wildfires and Power Outages Cause Disruptions for Scientists

Wildfires whipped up by hurricane-force winds have led to evacuations and precautionary power outages across California over the past few days. Major research institutions, including the University of California, Berkeley, endured their second blackout in a month. [Nature News] Editorial

Increase in Academics Leaving the UK Since Brexit Vote

After the 2016 Brexit referendum, in which voters decided to have the UK leave the European Union (EU), the number of academics from EU countries leaving the United Kingdom for other university jobs increased by almost half, according to Times Higher Education. [The Scientist] Editorial

PhD-turned-policy Insider Takes Over World’s Largest Science Society

in January 2020, the 46-year-old structural biologist Sudip Parikh will become the new CEO of AAAS (which publishes Science) as the 171-year-old association pursues its mission to advance science and serve society. [ScienceInsider] Editorial

NEW FGF Signaling: Understanding Function and Devising Therapeutic Tools
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