Neural Cell News Volume 13.23 | Jun 19 2019

TOP STORY

Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Scientists evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. They transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. [Cell Stem Cell] Abstract | Graphical Abstract

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Sensory Lesioning Induces Microglial Synapse Elimination via ADAM10 and Fractalkine Signaling

Researchers showed that whisker lesioning, known to dampen cortical activity, induced microglia-mediated synapse elimination. This synapse elimination was dependent on signaling by CX3CR1, the receptor for microglial fractalkine, but not complement receptor 3. [Nat Neurosci] Abstract

High-Frequency Activation of Nucleus Accumbens D1-MSNs Drives Excitatory Potentiation on D2-MSNs

The authors report a collateral excitation mechanism in which high-frequency, nucleus accumben core dopamine 1 (D1)-medium spiny neuron (MSN) activation caused long-lasting potentiation of excitatory transmission on dopamine receptor 2 (D2)-MSNs. They demonstrated that this form of plasticity required release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. [Neuron] Abstract | Graphical Abstract

Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration

Deletion of Rufy3 protected axons from degeneration, even in the presence of activated CASP3 that was competent to cleave endogenous substrates. Dephosphorylation of RUFY3 at residue S34 appeared required for axon degeneration, providing a potential mechanism for neurons to locally control caspase-driven degeneration. [Neuron] Abstract | Graphical Abstract

Oxidative Stress in Vagal Neurons Promotes Parkinsonian Pathology and Intercellular α-Synuclein Transfer

Severe oxidative stress resulted in enhanced production of oxidatively modified forms of α-synuclein, increased α-synuclein aggregation into oligomeric species and marked degeneration of dorsal motor nucleus of the vagus nerve (DMnX) neurons. Enhanced oxidative stress also affected neuron-to-neuron protein transfer, causing an increased spreading of α-synuclein from the DMnX toward more rostral brain regions. [J Clin Invest] Abstract | Full Article

Modeling Microcephaly with Cerebral Organoids Reveals a WDR62-CEP170-KIF2A Pathway Promoting Cilium Disassembly in Neural Progenitors

WDR62 ablation led to retarded cilium disassembly, long cilium, and delayed cell cycle progression leading to decreased proliferation and premature differentiation of neural progenitor cells. Mechanistically, WDR62 interacted with and promoted CEP170’s localization to the basal body of primary cilium, where CEP170 recruited microtubule-depolymerizing factor KIF2A to disassemble the cilium. [Nat Commun] Full Article

Mediator Complex Interaction Partners Organize the Transcriptional Network That Defines Neural Stem Cells

Researchers identified E-box transcription factor Tcf4 as a key regulator of neural stem cells. Tcf4 interacted with Mediator, colocalized with Mediator at super enhancers and regulated neurogenic transcription factor genes with super enhancers and broad H3K4me3 domains. [Nat Commun] Full Article

WDR45 Contributes to Neurodegeneration through Regulation of ER Homeostasis and Neuronal Death

At the cellular level, accumulation of endoplasmic reticulum (ER) proteins due to WDR45 deficiency resulted in increased ER stress and impaired ER quality control. The unfolded protein response was elevated through the ERN1/IRE1 or EIF2AK3/PERK pathway, and eventually led to neuronal apoptosis. Suppression of ER stress or activation of autophagy through MTOR inhibition alleviated cell death. [Autophagy] Abstract

The Intracellular Domain of CX3CL1 Regulates Adult Neurogenesis and Alzheimer’s Amyloid Pathology

Amyloid deposition and neuronal loss were significantly reduced when membrane-anchored CX3CL1 C-terminal fragment was overexpressed in Alzheimer’s 5xFAD mouse model. The reversal of neuronal loss in 5xFAD could be attributed to increased neurogenesis by CX3CL1-intracellular domain, as revealed by morphological and unbiased RNA-sequencing analyses. [J Exp Med] Abstract

Multiple Cancer Pathways Regulate Telomere Protection

Scientists found that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulated the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. They showed that both bRAF and ERK2 kinases phosphorylatd TRF1 in vitro and that these modifications were essential for TRF1 location to telomeres in vivo. [EMBO Mol Med] Full Article | Press Release | Graphical Abstract

α2-Chimaerin Is Essential for Neural Stem Cell Homeostasis in Mouse Adult Neurogenesis

Conditional deletion of α2-chimaerin in adult neural stem cells (NSCs) resulted in the premature differentiation of NSCs into intermediate progenitor cells (IPCs), which ultimately depleted the NSC pool and impaired neuron generation. Investigators revealed that α2-chimaerin-conditional knockout mice lacked a unique NSC subpopulation, termed Klotho-expressing NSCs, during the transition of NSCs to IPCs. [Proc Natl Acad Sci USA] Full Article

βII-Spectrin Promotes Mouse Brain Connectivity through Stabilizing Axonal Plasma Membranes and Enabling Axonal Organelle Transport

βII-spectrin-null neurons exhibited reduced axon growth, loss of actin-spectrin-based periodic membrane skeleton, and impaired bidirectional axonal transport of synaptic cargo. Scientists found that βII-spectrin associated with KIF3A, KIF5B, KIF1A, and dynactin, implicating spectrin in the coupling of motors and synaptic cargo. [Proc Natl Acad Sci USA] Abstract

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Neuronal Regulation of Immunity in the Skin and Lungs

The authors focus on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. [Trends Neurosci] Abstract

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Medicenna Presents Preliminary Top-Line Clinical Results from Their Phase IIb Trial of MDNA55 in Recurrent Glioblastoma

Medicenna Therapeutics Corp. presented preliminary top-line clinical results from their Phase IIb trial of MDNA55, an IL4-guided toxin, in patients with recurrent glioblastoma, the most common and uniformly fatal form of brain cancer. [Press release from Medicenna Therapeutics Corp. discussing research presented at the 2019 Immuno-Oncology Pharma Congress, Boston] Press Release

Adamas Announces Data Analysis Demonstrating GOCOVRI Reduces Both the Frequency and Duration of Daily Episodes of Troublesome Dyskinesia and OFF in Parkinson’s Disease

Adamas Pharmaceuticals, Inc. announced a retrospective data analysis from pooled Phase III trials of GOCOVRI^® extended release capsules were presented. GOCOVRI^® is the first and only medicine approved by the FDA for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications. [Press release from Adamas Pharmaceuticals, Inc. discussing research presented at the 2019 International Association of Parkinsonism and Related Disorders (IAPRD) World Congress, Montreal] Press Release

Voyager Therapeutics Announces Restructured Gene Therapy Relationship with Sanofi Genzyme and Portfolio Update

Voyager Therapeutics, Inc. announced a restructuring of its gene therapy relationship with Sanofi Genzyme. Under the terms of the agreement, Voyager gains worldwide rights to the VY-HTT01 Huntington’s disease program and ex-US rights to the VY-FXN01 Friedreich’s ataxia program. [Voyager Therapeutics, Inc.] Press Release

IntelGenx Announces Addition of Peterborough’s Kawartha Centre as Montelukast VersaFilm^® Phase IIa Clinical Trial Site

IntelGenx Corp. announced that the Kawartha Centre has agreed to participate in IntelGenx’s Montelukast VersaFilm^® Phase IIa BUENA clinical trial in patients with mild to moderate Alzheimer’s Disease. [IntelGenx Corp.] Press Release

Regorafenib to Be Tested in Brain Cancer Patients in Multi-Arm Cooperation Trial

Bayer announced that the regorafenib arm of the platform trial “GBM AGILE” opened for enrollment in the US for patients with newly diagnosed and recurrent glioblastoma (GBM), the most aggressive and common form of primary brain cancer. This marks the start of an international, innovative study with a seamless Phase II/III design set up to rapidly identify effective therapies for patients with GBM; sponsored by the Global Coalition for Adaptive Research, with Bayer supporting the trial with drug supply and grants. [Bayer AG] Press Release

Canada’s Largest Dementia Research Network – the Canadian Consortium on Neurodegeneration in Aging – Enters Its Second Phase

The Canadian Consortium on Neurodegeneration in Aging’s main partner – the Canadian Institutes of Health Research – announced its renewal for a second phase. The scientific leadership and additional partner organizations will continue to support 19 national teams of researchers in advancing the science on neurodegenerative diseases, including new projects focused on sleep and dementia. [The Canadian Consortium on Neurodegeneration in Aging] Press Release

Researcher Receives $4 Million Grant to Use Brain Imaging, Genomic Data to Better Predict Mental Health Disorders

Vince Calhoun, university Professor of Psychology at Georgia State University and director of the Center for Translational Research in Neuroimaging and Data Science, has received nearly $4 million from the National Institutes of Health’s National Institute of Mental Health to develop new models that use brain imaging and genomic data to better predict mental health disorders. [Georgia State University] Press Release

Mill Creek Life Sciences Receives Grant from Regenerative Medicine Minnesota for Development of Dendritic Cell Vaccine

Mill Creek Life Sciences, LLC. has received a one-year $100,000 grant from Regenerative Medicine Minnesota titled: “Development of Technology for the Large-scale Production of a Novel Dendritic Cell Vaccine for the Treatment of Glioblastoma.” [Mill Creek Life Sciences, LLC. (PR Newswire Association LLC.)] Press Release

Beactica Wins Grant to Develop Combination Therapy for Glioblastoma

Beactica AB announced that it has been awarded a grant of 2.8 million Swedish Krona from SweLife and Medtech4Health for its project focused on finding effective therapies for glioblastoma, an aggressive form of brain cancer. The compound developed by Beactica, BEA-17, recently showed indication of efficacy in an in vivo proof-of-principle study. [Beactica AB] Press Release

Hong Kong Researchers Forge Ties With Mainland China Even as Protesters Fight for Autonomy

After a series of massive protests by Hong Kong’s residents, including many academics, the leaders of the semiautonomous Chinese city last week shelved controversial legislation that would have allowed people there to be extradited to mainland China. But even as that battle to preserve independence continues, Hong Kong’s researchers are forging closer ties with the mainland. [ScienceInsider] Editorial

Africa’s Science Academy Leads Push for Ethical Data Use

The African Academy of Sciences has started work on the continent’s first cross-disciplinary guidelines on how to collect, store and share research data and specimens in ways that protect study participants from exploitation and benefit African citizens. [Nature News] Editorial

NEW Keystone Symposia: Cancer Stem Cells: Advances in Biology & Clinical Translation
October 13-17, 2019
Hong Kong, China

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NEW Postdoctoral Scientist – Glioma Organoids (Rutgers Cancer Institute of New Jersey)

NEW Research Lab Specialist – Tumor Microenvironment & Cell Behavior (University of Southern California)

Tenure Track Faculty Positions – Neuropharmacology or Neurodegeneration (The University of Tennessee Health Science Center)

Postdoctoral Researcher – Retinal Stem Cell Biology (NIH National Eye Institute)

Postdoctoral Research Fellow – Molecular Neuroscience (Fred Hutchinson Cancer Research Center)

Postdoctoral Fellow – Nanoparticle-Based Therapeutic Delivery to the Brain (Johns Hopkins School of Medicine)

Postdoctoral Researcher – Brain Cancer Research (University of Alabama at Birmingham)

Postdoctoral Position – Neuropsychiatric Disorders (Stanford University)

Postdoctoral Fellow – Epigenetic Regulation of Neuronal Identity (The Helmholtz Pioneer Campus)

Associate Professor – Translational Psychiatry (Aarhus University)

Postdoctoral Positions – Neuroscience (Weill Cornell Medical College)

Postdoctoral Fellow – Ion Channel & Neuroscience Research (Johns Hopkins University)

Postdoctoral Fellow/Research Assistant Positions – Glioma Research (NIH National Cancer Institute Laboratory of Pathology)

Postdoctoral Position – Retinal Stem Cell Biology (Johns Hopkins University)

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