Neural Cell News Volume 13.25 | Jul 3 2019

TOP STORY

Allele-Selective Transcriptional Repression of Mutant HTT for the Treatment of Huntington’s Disease

Using patient-derived fibroblasts and neurons, scientists demonstrated that zinc finger protein transcription factors (ZFP-TFs) selectively repressed >99% of Huntington’s disease (HD)-causing alleles over a wide dose range while preserving expression of >86% of normal alleles. Other CAG-containing genes were minimally affected, and virally delivered ZFP-TFs were active and well tolerated in HD neurons. [Nat Med] Abstract | Press Release | Editorial

(Ranked by impact factor of the journal)

Regulation of Energy Expenditure by Brainstem GABA Neurons

Investigators report that a population of GABAergic neurons in the dorsolateral portion of the dorsal raphe nucleus (DRN), hereafter DRN^Vgat neurons, were activated by ambient heat and bidirectionally regulated energy expenditure through changes in both thermogenesis and locomotion. They found that DRN^Vgat neurons innervated brown fat via a descending projection to the raphe pallidus. [Cell] Abstract | Press Release | Graphical Abstract

Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD

To yield insights into the role of stress granules (SGs) in pathophysiology, researchers performed a high-content screen to identify small molecules that alter SG properties in proliferative cells and human induced pluripotent stem cell-derived motor neurons. They showed that several hit compounds could prevent the RNA-dependent recruitment of the ALS-associated RNA-binding proteins TDP-43, FUS, and HNRNPA2B1 into SGs. [Neuron] Abstract | Press Release | Graphical Abstract

Memo1-Mediated Tiling of Radial Glial Cells Facilitates Cerebral Cortical Development

The authors showed that mediator of cell motility 1 (Memo1) was a critical determinant of radial glial tiling during neocortical development. Memo1 deletion or knockdown led to hyperbranching of radial glial cell (RGC) basal processes and disrupted RGC tiling, resulting in aberrant radial unit assembly and neuronal layering. [Neuron] Abstract | Press Release | Graphical Abstract

Myc Targeted CDK18 Promotes ATR and Homologous Recombination to Mediate PARP Inhibitor Resistance in Glioblastoma

Investigators showed that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells generated sensitivity to PARP inhibitors via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification were not sensitive. [Nat Commun] Full Article

Motor Dysfunction and Neurodegeneration in a C9orf72 Mouse Line Expressing Poly-PR

Scientists generated a transgenic mouse line that expressed poly-PR (GFP-PR₂₈) specifically in neurons. GFP-PR₂₈ homozygous mice showed decreased survival time, while the heterozygous mice showed motor imbalance, decreased brain weight, loss of Purkinje cells and lower motor neurons, and inflammation in the cerebellum and spinal cord. [Nat Commun] Full Article

Neuronal Soma-Derived Degradative Lysosomes Are Continuously Delivered to Distal Axons to Maintain Local Degradation Capacity

By time-lapse imaging of cortical neurons in microfluidic devices and standard dishes, the authors revealed that soma-derived degradative lysosomes rapidly influx into distal axons and target to autophagosomes and Parkinson disease-related α-synuclein cargos for local degradation. Impairing lysosome axonal delivery induced an aberrant accumulation of autophagosomes and α-synuclein cargos in distal axons. [Cell Rep] Full Article | Graphical Abstract

KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels

Researchers showed KCC2 interacted with Task-3 channels and was required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. [Cell Rep] Full Article | Graphical Abstract

Long Noncoding RNA NEAT1 Mediates Neuronal Histone Methylation and Age-Related Memory Impairment

Scientists investigated how the long noncoding RNA NEAT1 epigenetically contributed to hippocampus-dependent, long-term memory formation using a combination of transcriptomics, RNA-binding protein immunoprecipitation, CRISPR-mediated gene activation, and behavioral approaches. [Sci Signal] Abstract | Press Release

Optochemogenetics Stimulation of Transplanted iPS-NPCs Enhances Neuronal Repair and Functional Recovery after Ischemic Stroke

Investigators tested the hypothesis that selective excitation of transplanted induced pluripotent stem cell-derived neural progenitor cells (iPS-NPCs) could recapitulate an activity-enriched microenvironment that confers regenerative benefits for the treatment of stroke. [J Neurosci] Abstract | Press Release

Self-Organized Synchronous Calcium Transients in a Cultured Human Neural Network Derived from Cerebral Organoids

Self-organized neuronal network formation was observed following a dissociation culture of human embryonic stem cell-derived cerebral organoids. The spontaneous individual and synchronized activity of the network was measured via calcium imaging, and subsequent analysis enabled the examination of detailed cell activity patterns, providing simultaneous raster plots, cluster analyses, and cell distribution data. [Stem Cell Reports] Full Article | Editorial | Graphical Abstract

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The Roles of Perineuronal Nets and the Perinodal Extracellular Matrix in Neuronal Function

Recent work has revealed the importance of perineuronal nets (PNNs) in controlling plasticity in the CNS. Digestion, blocking or removal of PNNs influences functional recovery after a variety of CNS lesions. PNNs have further been shown to be involved in the regulation of memory and have been implicated in a number of psychiatric disorders. [Nat Rev Neurosci] Abstract

Neuroinflammatory Pathways as Treatment Targets and Biomarkers in Epilepsy

Investigators focus on the understanding of the IL-1 receptor–Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-β signaling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities. [Nat Rev Neurol] Abstract

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Emerald Health Pharmaceuticals Demonstrates Repair of Nerve Damage Related to Multiple Sclerosis

Emerald Health Pharmaceuticals Inc. presented preclinical data on its clinical-stage lead drug product candidate, EHP-101, demonstrating its remyelination activity, or the ability to repair the nerves damaged in a multiple sclerosis murine model. [Press release from Emerald Health Pharmaceuticals Inc. (GlobeNewswire, Inc.) discussing research presented at the 29^th Annual Symposium of the International Cannabinoid Research Society (ICRS), Bethesda] Press Release

Biogen Announces New Data Further Establishing SPINRAZA^® (Nusinersen) as a Foundation of Care in Spinal Muscular Atrophy for a Broad Range of Patients

Biogen announced new results from the NURTURE study, adding data to the longest study of spinal muscular atrophy in pre-symptomatic infants. [Press release from Biogen discussing research presented at the Cure SMA Annual SMA Conference, Anaheim and the 5^th Congress of the European Academy of Neurology (EAN), Oslo] Press Release

ProMIS Neurosciences’ PMN310 Shows Greater Therapeutic Potential vs. Other Amyloid-Beta-Directed Antibodies

ProMIS’ Chief Development Officer Dr. Johanne Kaplan presented data showing that PMN310 possesses superior selectivity for amyloid beta (Aβ) toxic oligomers and improved therapeutic potential compared with other Aβ-directed antibodies. [Press release from ProMIS Neurosciences, Inc. discussing research presented at Keystone Symposium on Neurodegenerative Diseases, Keystone] Press Release

Dr. Madeline Lancaster talks about her groundbreaking work generating ‘mini-brains’. Watch Now

University Partners with Bukwang Pharmaceutical Company to Develop New Drug Treatment for Parkinson’s Disease

The University of Dundee‘s Drug Discovery Unit (DDU) has announced a multi-million-pound partnership with Korean-based Bukwang Pharmaceutical Company in a bid to develop a new drug treatment for Parkinson’s disease. This announcement builds upon existing drug discovery partnerships the DDU has with Takeda and GSK. [The University of Dundee] Press Release

Targeting Nerve Cell Batteries to Slow Parkinson’s Progression

As part of their Virtual Biotech, Parkinson’s UK is partnering with NRG Therapeutics Ltd to identify new molecules that can enter the brain and support the mitochondria – the batteries that power brain cells. If successful, these protective molecules could provide a safe and effective new treatment that will protect brain cells and slow the progression of Parkinson’s. [Parkinson’s UK] Press Release

Ziopharm Oncology Initiates Phase II Trial Evaluating Combination Therapy of Controlled IL-12 with Libtayo^® (Cemiplimab-Rwlc) to Treat Patients with Recurrent Glioblastoma

Ziopharm Oncology, Inc. announced the initiation of a Phase II clinical trial evaluating controlled IL-12, in combination with PD-1 antibody Libtayo^® for the treatment of recurrent or progressive glioblastoma multiforme in adults. The multi-center trial will be conducted at approximately ten hospitals specializing in the treatment of brain cancers in the United States. [Ziopharm Oncology, Inc.] Press Release

vTv Therapeutics Initiates Phase II Clinical Trial Evaluating Azeliragon in Patients with Mild Alzheimer’s Disease and Type 2 Diabetes

vTv Therapeutics Inc. announced that the first patient has been screened for the Phase II proof of concept study evaluating the safety and efficacy of azeliragon in patients with mild Alzheimer’s disease and type 2 diabetes. [vTv Therapeutics Inc.] Press Release

Medicortex Announces Receiving a 1.1 Million Dollars Research Grant from the US Department of Defense

Medicortex Finland Oy announced the award of a 1.1 million dollars grant from the USA Department of Defense. The grant provides funding for continued clinical development of the company’s diagnostic kit ProbTBI^™ for rapid detection of mild traumatic brain injury and concussion. [Medicortex Finland Oy (Business Wire, Inc.)] Press Release

Therapeutic Solutions International Obtains Exclusive License for Patented Clinical Stage Adult Stem Cell for Treatment of Military and Sports Brain Injuries

Therapeutics Solutions International, Inc. announced recently signing of a license agreement providing exclusive rights to a patented adult stem cell for development of therapeutics in the area of chronic traumatic encephalopathy and traumatic brain injury. [Therapeutics Solutions International, Inc.] Press Release

FDA Enforcement Actions Plummet under Trump

From monitoring clinical trials and approving medicines and vaccines, to ensuring the safety of blood transfusions, medical devices, groceries, and more, the FDA is one of the nation’s most vital watchdogs. By several measures, however, FDA’s compliance and enforcement actions have plummeted since President Donald Trump took office, Science has found. [ScienceInsider] Editorial

Germany’s Prestigious Max Planck Society Conducts Huge Bullying Survey

Most of the scientists who work for one of the world’s richest and most prestigious basic research organizations, the Max Planck Society (MPS) in Germany, have pride and trust in their institutes — but cases of sexual discrimination and bullying occur regularly, and nearly half of foreign scientists working for the MPS don’t feel they fit in. [Nature News] Editorial

NEW The Brain Mosiac: Cellular Heterogeneity in the CNS (2^nd edition)
October 10-11, 2019
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