Neural Cell News Volume 13.49 | Dec 18 2019

TOP STORY

Microglia Monitor and Protect Neuronal Function via Specialized Somatic Purinergic Junctions

Researchers identified an interaction site between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia-neuron junctions possessed specialized nanoarchitecture optimized for purinergic signaling. [Science] Abstract

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Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7

Transcriptome analysis of spinocerebellar ataxia type 7 (SCA7) mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of down-regulated genes yielded Sirtuin 1 (Sirt1) target sites, and investigators observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD⁺ depletion. [Neuron] Abstract | Graphical Abstract | Press Release

Molecular Tuning of the Axonal Mitochondrial Ca²⁺ Uniporter Ensures Metabolic Flexibility of Neurotransmission

Scientists demonstrated that, whereas mitochondrial Ca²⁺ uptake requires elevated extramitochondrial Ca²⁺ in non-neuronal cells, axonal mitochondria readily took up Ca²⁺ in response to small changes in external Ca²⁺.” [Neuron] Abstract | Graphical Abstract

Computational Modeling Demonstrates That Glioblastoma Cells Can Survive Spatial Environmental Challenges Through Exploratory Adaptation

TResearchers investigated whether exploratory adaption explained how glioblastoma cells from different anatomic regions of the tumor cope with micro-environmental pressures. They introduced new notions of phenotype and phenotype distance, and determined probable spatial-phenotypic trajectories based on patient data. [Nat Commun] Full Article

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

The authors showed that adeno-associated virus serotype 9-mediated delivery of Stasimon-a gene encoding an endoplasmic reticulum-resident transmembrane protein regulated by survival motor neuron-improved motor function in a mouse model of spinal muscular atrophy through multiple mechanisms. In proprioceptive neurons, Stasimon overexpression prevented the loss of afferent synapses on motor neurons and enhanced sensory-motor neurotransmission. [Cell Rep] Full Article | Graphical Abstract

BPTF Regulates Growth of Adult and Pediatric High-Grade Glioma through the MYC Pathway

Using a two-step, in vitro/in vivo epigenomic shRNA inhibition screen, scientists determined the chromatin re-modeler BPTF to be a key regulator of adult high-grade gliomas (HGG) growth. They demonstrated that BPTF knockdown decreased HGG growth in multiple pediatric HGG models as well. [Oncogene] Abstract

Primary Cilia Mediate Mitochondrial Stress Responses to Promote Dopamine Neuron Survival in a Parkinson’s Disease Model

The authors showed that mitochondrial stress, caused by respiratory complex inhibitors and excessive fission, robustly stimulated ciliogenesis in different types of cells including neuronal cells. Mitochondrial stress-induced ciliogenesis was mediated by mitochondrial reactive oxygen species generation, subsequent activation of AMP-activated protein kinase and autophagy. [Cell Death Dis] Full Article

Mutant C9orf72 Human iPSC-Derived Astrocytes Cause Non-Cell Autonomous Motor Neuron Pathophysiology

Researchers used a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. They showed that mutant astrocytes both recapitulate key aspects of C9orf72-related amyotrophic lateral sclerosis pathology and, upon co-culture, caused motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na⁺ and K⁺ currents. [Glia] Full Article

Modeling Heme-Mediated Brain Injury Associated with Cerebral Malaria in Human Brain Cortical Organoids

Investigators determined the effects of heme on induced pluripotent stem cells and a three-dimensional cortical organoid system and assessed apoptosis and differentiation. They evaluated biomarkers associated with heme-induced brain injury, including a pro-inflammatory chemokine, CXCL-10, and its receptor, CXCR3, brain-derived neurotrophic factor and a receptor tyrosine-protein kinase, ERBB4, in the organoids. [Sci Rep] Full Article

Tissue-Type Plasminogen Activator-Primed Human iPSC-Derived Neural Progenitor Cells Promote Motor Recovery After Severe Spinal Cord Injury

Scientists report a method that takes advantage of the growth factor-like and anti-inflammatory activities of the fibrinolysis protease, tissue plasminogen activator tPA, without effects on hemostasis. They demonstrated that conditioning induced pluripotent stem cell-derived neural progenitor cells with enzymatically-inactive tissue-type plasminogen activator, prior to grafting into a T3 lesion site in a clinically relevant severe spinal cord injury model, significantly improved motor outcomes. [Sci Rep] Full Article

Brain Angiotensin Type-1 and Type-2 Receptors: Cellular Locations Under Normal and Hypertensive Conditions

A brain angiotensin-II type-1 receptors(AT1Rs)-tdTomato reporter mouse strain was crossed with our previously described AT2R-eGFP reporter mouse strain to yield a novel dual AT1aR/AT2R reporter mouse strain, which allowed scientists to determine that AT1aR and AT2R were primarily localized to different populations of neurons in brain regions controlling cardiovascular, fluid, and metabolic homeostasis. [Hypertens Res] Abstract

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Neuroimmune Circuits in Inter-Organ Communication

The authors focus on the impact of bidirectional neuroimmune interactions in tissue biology, organ physiology and embryonic development. They explore how this fast-evolving field is redefining the tenets of inter-organ and intergenerational communications. [Nat Rev Immunol] Abstract

Cerebral Amyloid Angiopathy and Alzheimer Disease – One Peptide, Two Pathways

The pathogenic pathways of cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) intersect at the levels of amyloid-β generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Investigators review the evidence for and the pathogenic implications of interactions between CAA and AD. [Nat Rev Neurol] Abstract

Fiery Cell Death: Pyroptosis in the Central Nervous System

Pyroptosis is mediated directly by the recently identified family of pore-forming proteins known as gasdermins, the best characterized of which is gasdermin D. Scientists discuss molecular mechanisms that drive pyroptosis, evidence for pyroptosis within the CNS, and emerging therapeutic strategies for its inhibition in the context of neurological disease. [Trends Neurosci] Abstract

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Axsome Therapeutics Announces AXS-05 Achieves Primary Endpoint in GEMINI Phase III Trial in Major Depressive Disorder

Axsome Therapeutics, Inc. announced that AXS-05, a novel, oral, investigational NMDA receptor antagonist with multimodal activity, met the primary endpoint and rapidly and significantly improved symptoms of depression in the GEMINI Phase III trial in major depressive disorder. [Axsome Therapeutics, Inc.] Press Release

Chondrial Therapeutics Announces Dosing of First Patients in Phase I Clinical Program of CTI-1601 for Treatment of Friedreich’s Ataxia and CTI-1601 Granted Rare Pediatric Disease Designation and Fast Track Designation by US FDA

Chondrial Therapeutics announced that the first patients have been dosed in a Phase I clinical trial to evaluate the safety and tolerability of single ascending doses of CTI-1601. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin to patients with Friedreich’s ataxia, who have decreased levels of frataxin. [Chondrial Therapeutics] Press Release

New Grant Will Fund Clinical Trial of a Novel Approach to Treating Alzheimer’s

With a new grant from the Alzheimer’s Association, a team of researchers from Brown University, Butler Hospital and the Miriam Hospital will conduct a Phase I clinical trial of a drug that could potentially provide a new avenue for the treatment of Alzheimer’s disease. [EurekAlert!] Press Release

Spending Bill Boosts US Science Budgets, Unlocks Gun Research

For the 2020 fiscal year, most US research agencies will receive a funding increase, according to details of a spending bill released by Congress. A total of $2.8 billion of the NIH budget, a boost of $330 million over this year, will be earmarked for Alzheimer’s research, with another $12.5 million for firearm injury and mortality protection research. [The Scientist] Editorial

The Top Retractions of 2019

Another year, another 1,433 (and counting) retractions. The tenth year of Retraction Watch’s existence included-as is often the case-a new record, some impressive numbers, and some bizarre stories. But it also included some exemplary behavior. [The Scientist] Editorial

NIH Considering New Recommendations on Sexual Harassment Policies

Recommendations put forth by the Working Group on Changing the Culture to End Sexual Harassment include requiring NIH-funded institutions to notify the agency within two weeks when a grant recipient is found guilty of sexual misconduct, barring confirmed harassers from serving on NIH advisory councils, and mandating that grant applicants report sexual harassment findings against them. [The Scientist] Editorial

NEW Pain: Aligning the Target and Somatosensation: From Detection to Perception
February 2-5, 2020
Keystone, Colorado, United States

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