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Article
| Open AccessRe-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states
Glioblastoma (GBM) cells can infiltrate into the tumour microenvironment (TME) and contribute to recurrence. Here, the authors analyse primary and recurrent GBMs and their TME using single-nucleus and spatial transcriptomics, revealing tissue states defined by the combinations of neoplastic and non-neoplastic cells, which could be therapeutic targets.
- Osama Al-Dalahmah
- , Michael G. Argenziano
- & Peter Canoll
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Article
| Open AccessGut microbiome dysbiosis across early Parkinson’s disease, REM sleep behavior disorder and their first-degree relatives
Microbiota-gut-brain axis may play an important role in Parkinson’s disease (PD). Here, the authors assess gut microbiota in early PD, REM sleep behaviour disorder (RBD) and first-degree relatives of RBD and show PD-like gut dysbiosis occurs in RBD and their first-degree relatives.
- Bei Huang
- , Steven W. H. Chau
- & Yun Kwok Wing
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Article
| Open AccessA computational analysis of mouse behavior in the sucrose preference test
The sucrose preference test is one of the most widely used paradigms in behavioral neuroscience. Here, authors identify previously unrecognized behavioral subcomponents that can influence how it is interpreted.
- Jeroen P. H. Verharen
- , Johannes W. de Jong
- & Stephan Lammel
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Article
| Open AccessSoluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy
Brain microvascular dysfunction occurs in Alzheimer’s disease and other taupathies. Here the authors show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy, and that it contributes to vascular deficits in these mice.
- Stacy A. Hussong
- , Andy Q. Banh
- & Veronica Galvan
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Article
| Open AccessSingle-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
Mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) cause autosomal dominant AD (ADAD). Here, the authors perform single-nucleus RNA-sequencing of ADAD and other disease risk modifying variant carriers and report altered expression states of specific brain cell types.
- Logan Brase
- , Shih-Feng You
- & Oscar Harari
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Article
| Open AccessIntegrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology
The causes of ALS remain unclear with many proposed pathomechanisms. Here, the authors integrate iPSC-derived motor neuron and post-mortem datasets and identify a heightened DNA damage response accompanied by accumulation of somatic mutations in ALS.
- Oliver J. Ziff
- , Jacob Neeves
- & Rickie Patani
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Article
| Open AccessDisrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease
ESCRT-III is involved in the endolysosomal system and disturbed in neurodegenerative diseases. Here the authors show that disruption of an interaction between ESCRT-III member CHMP2B and α-synuclein by a peptide inhibitor mitigates neurodegeneration in Parkinson’s disease models.
- Satra Nim
- , Darren M. O’Hara
- & Philip M. Kim
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Article
| Open AccessThe basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice
While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here, authors show the critical role of the BLA-ACC pathway in pain and emotional processing, and their comorbidity.
- Léa J. Becker
- , Clémentine Fillinger
- & Ipek Yalcin
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Article
| Open AccessPiezo2 regulates colonic mechanical sensitivity in a sex specific manner in mice
Piezo2 in mucosa and primary afferents mediates colonic mechanical sensation. Here the authors show that activation of Piezo2 regulates colonic mechanical sensitivity in a sex dependent manner.
- Jonathan Madar
- , Namrata Tiwari
- & Liya Y. Qiao
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Article
| Open AccessPlasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders
Plasma neurodegeneration biomarkers are increasingly utilized to predict neurological disease. Here, authors show in different neurological disorders associations between plasma neurodegeneration biomarker concentrations and various measures of glymphatic and meningeal lymphatic functions.
- Per Kristian Eide
- , Aslan Lashkarivand
- & Henrik Zetterberg
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Article
| Open AccessGlucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism
GBA1 mutations cause Gaucher’s disease and are the strongest risk factor for Parkinson’s disease. Using stable cell lines and patient iPSCs, the authors show mitochondrial localization of GBA1, which may affect neurodegenerative disease risk.
- Pascale Baden
- , Maria Jose Perez
- & Michela Deleidi
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Article
| Open AccessLateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula
The mechanism underlying caffeine consumption inversely correlation with depression is unclear. Here, authors identified adenosine A2A receptor in the lateral septum mediating depressive symptoms via direct outputs to the habenula and the hypothalamus.
- Muran Wang
- , Peijun Li
- & Wei Guo
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Article
| Open AccessHematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy
Cerebral adrenoleukodystrophy (CALD) is a demyelinating disease caused by loss of ABCD1 gene function. Here the authors investigate white matter structural and microvascular changes in boys with CALD that received gene therapy with autologous hematopoietic stem-cells.
- Arne Lauer
- , Samantha L. Speroni
- & Patricia L. Musolino
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Article
| Open AccessBuffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional modulator MECP2. Here, the authors measured transcription rate and mRNA half-life changes in RTT patient-derived neurons to show transcription rate buffered by mRNA half-life changes.
- Deivid C. Rodrigues
- , Marat Mufteev
- & James Ellis
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Perspective
| Open AccessAn aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
In this perspective, the authors hypothesise that glial senescence, requiring senescent microglia burden, perpetuates further aging, Alzheimer’s pathologies, and senescence. Increasing glial senescence is proposed as necessary to drive individuals from healthy cognition into cognitive decline and dementia.
- Victor Lau
- , Leanne Ramer
- & Marie-Ève Tremblay
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Article
| Open AccessImmunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer’s disease
Acid sphingomyelinase (ASM) is a sphingolipid metabolizing enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide, and previous work has shown it is upregulated in models of Alzheimer’s disease. Here the authors demonstrate in a mouse model of Alzheimer’s disease that antibody-based immunotherapy targeting plasma ASM resulted in attenuated neuropathological features by suppressing pathogenic Th17 cells.
- Byung Jo Choi
- , Min Hee Park
- & Jae-sung Bae
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Article
| Open AccessAndrogens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination
Androgen effects have been poorly studied in demyelinating diseases in females. Here, authors show androgen requirement for proper myelin regeneration in females and the critical need to consider male-female differences in multiple sclerosis patients.
- Amina Zahaf
- , Abdelmoumen Kassoussi
- & Elisabeth Traiffort
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Article
| Open AccessRescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer’s disease
Altered Ca2+ signaling is involved in the pathogenesis of Alzheimer’s disease. Here, the authors show Ca2+ hypoactivity in astrocytes at plaque deposition onset related to reduced expression of the Ca2+ sensor STIM1 and impaired synaptic plasticity that was rescued by STIM1 overexpression in astrocytes.
- Annamaria Lia
- , Gabriele Sansevero
- & Micaela Zonta
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Article
| Open AccessCocaine induces locomotor sensitization through a dopamine-dependent VTA-mPFC-FrA cortico-cortical pathway in male mice
The prefrontal cortex is involved in cocaine abuse disorders. Here, the authors show that cocaine suppresses frontal association cortex (FrA) in awake mice and induces locomotor sensitization through a dopamine dependent VTA-vmPFC-FrA pathway.
- Lun Wang
- , Min Gao
- & Zhuan Zhou
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Article
| Open AccessAberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice
Cajal-Retzius neurons number drastically decreases during postnatal life. Here, authors show that their programmed death is required for the construction of functional hippocampal circuits and memory with aberrant survival leading to gamma rhythmopathies and susceptibility to seizures.
- Martina Riva
- , Stéphanie Moriceau
- & Alessandra Pierani
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Article
| Open AccessN-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model
Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.
- Stefano Suzzi
- , Tommaso Croese
- & Michal Schwartz
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Article
| Open AccessTyrosyl-tRNA synthetase has a noncanonical function in actin bundling
Mutations in tRNA ligases, essential components of the translational machinery, are associated with Charcot-Marie-Tooth peripheral neuropathy, but the mechanistic details are not known. The authors report that the tyrosyl-tRNA synthetase is an evolutionary-conserved F-actin organizer, and dysregulation of this function is associated with the disorder.
- Biljana Ermanoska
- , Bob Asselbergh
- & Albena Jordanova
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Article
| Open AccessChemogenetic attenuation of cortical seizures in nonhuman primates
Pharmacological and surgical treatments of epilepsy can have unsatisfactory outcomes, so a more targeted and on-demand approach is desirable. Here, the authors demonstrate the usage of inhibitory chemogenetics in male nonhuman primates to attenuate the magnitude and spread of cortical seizures and subsequent body convulsions.
- Naohisa Miyakawa
- , Yuji Nagai
- & Takafumi Minamimoto
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Article
| Open AccessEndogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration
Expression of Drosophila or human endogenous retroviruses (ERVs) is sufficient to cause TDP-43 protein aggregation, and viral transmission of the ERVs triggers TDP-43 pathology in recipient cells. This mechanism may underly spread of neurodegenerative effects in a Drosophila model.
- Yung-Heng Chang
- & Josh Dubnau
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Article
| Open AccessSREBP modulates the NADP+/NADPH cycle to control night sleep in Drosophila
Mechanisms underlying sleep dysfunctions in neurodevelopmental disorders remain elusive. Here, authors use a fly model for the CYFIP haploinsufficiency to show that increased SREBP activity impairs the NADP+/NADPH homeostasis inducing sleep deficits.
- Vittoria Mariano
- , Alexandros K. Kanellopoulos
- & Claudia Bagni
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Article
| Open AccessAn open label, non-randomized study assessing a prebiotic fiber intervention in a small cohort of Parkinson’s disease participants
This study found that a prebiotic intervention was well-tolerated and safe, beneficially changed the microbiome, decreased inflammation and a marker of neurodegeneration, with possible clinical effects in Parkinson’s disease (PD) patients. This study offers the rationale for further investigations using prebiotic fibers in PD.
- Deborah A. Hall
- , Robin M. Voigt
- & Ali Keshavarzian
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Article
| Open AccessRescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub
The 16p11.2 duplication confers risk for autism and schizophrenia, but the disease mechanisms are unknown. Here, the authors use proteomics to show dysregulation of synaptic and epilepsy-associated protein networks in the cortex of model mice, and demonstrate that correcting Prrt2 gene dosage rescues circuit hypersynchrony and behavioural phenotypes.
- Marc P. Forrest
- , Marc Dos Santos
- & Peter Penzes
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Article
| Open AccessRobust odor identification in novel olfactory environments in mice
Detecting relevant odours from background odours is important for animal behaviour. Here the authors design a task to study this process in mice.
- Yan Li
- , Mitchell Swerdloff
- & Gonzalo H. Otazu
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Article
| Open AccessElectroacupuncture improves swallowing function in a post-stroke dysphagia mouse model by activating the motor cortex inputs to the nucleus tractus solitarii through the parabrachial nuclei
Difficulty swallowing after stroke and the neural circuitry underlying this is not fully understood. Here the authors demonstrate, using a mouse model, a potential neural circuit mechanism for effects of electroacupuncture on swallowing behaviour in post-stroke dysphagia.
- Lulu Yao
- , Qiuping Ye
- & Nenggui Xu
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Article
| Open AccessSingle-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice
Oligodendrocytes have been increasingly shown to be involved in Alzheimer’s disease (AD). Here, the authors perform single-cell RNA-sequencing on APP NL-G-F mice and describe a disease-associated oligodendrocyte (DAO) population. They find inhibition of Erk1/2 signaling in DAOs rescues impaired axonal myelination and cognitive decline in an AD mouse model.
- Hanseul Park
- , Byounggook Cho
- & Jongpil Kim
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Article
| Open AccessSegmental motor recovery after cervical spinal cord injury relates to density and integrity of corticospinal tract projections
How the segmental innervation of upper limb muscles recovers after spinal cord injury is not fully understood. Here the authors show associations between corticospinal tract sparing and upper extremity recovery in spinal cord injury.
- Gustavo Balbinot
- , Guijin Li
- & Jose Zariffa
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Article
| Open AccessSynchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain
Increased low frequency cortical oscillations are observed in neuropathic pain. Here the authors perform Ca2+ imaging of DRG sensory neurons in a mouse model of neuropathic pain, and show that synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations are observed.
- Chao Chen
- , Linlin Sun
- & Peifu Tang
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Article
| Open AccessCryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a genetic mutation in the huntingtin gene (HTT). Here, cryo electron tomography provides insights into the morphology of the cells derived from patients with HD and mouse models of the disease.
- Gong-Her Wu
- , Charlene Smith-Geater
- & Wah Chiu
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Article
| Open AccessFTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke
The mechanisms behind how vascular repair is regulated after ischemic stroke are yet to be elucidated. Here, the authors describe that a circular RNA interacts with FTO to promote vascular repair following stroke in mice and primates via mediating m6 A modification.
- Bin Li
- , Wen Xi
- & Honghong Yao
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Article
| Open AccessGold nanoparticle-enhanced X-ray microtomography of the rodent reveals region-specific cerebrospinal fluid circulation in the brain
Cerebrospinal fluid (CSF) is essential for brain development. Here, the authors use gold nanoparticle enhanced X-ray microtomography to map CSF distribution in post-natal rodents and describe particle size-dependent CSF pathways that transport CSF into the brain parenchyma of rodents.
- Shelei Pan
- , Peter H. Yang
- & Jennifer M. Strahle
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Article
| Open AccessIntegrative genetic analysis illuminates ALS heritability and identifies risk genes
ALS is somewhat heritable, but the genetic basis is not completely understood. Here, the authors identify alterations in splicing in neurons associated with amyotrophic lateral sclerosis and uncover several associated genetic loci, with a potential link to nuclear pore defects.
- Salim Megat
- , Natalia Mora
- & Luc Dupuis
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Article
| Open AccessTranscriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease
In human and mouse models of Huntington’s disease, Matsushima, Pineda et al. show, using snRNAsequencing, the two axes defining identities of striatal projection neurons are multiplexed and differentially compromised, calling for distinct therapies.
- Ayano Matsushima
- , Sergio Sebastian Pineda
- & Ann M. Graybiel
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Article
| Open AccessInterleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection
Il-13 is expressed in neurons and IL-13 ko causes memory impairment. Here, authors show that IL-13 and its receptor IL-13Ra1 are pre- and post-synaptic proteins, respectively, involved in synaptic signaling, plasticity and neuroprotection.
- Shun Li
- , Florian olde Heuvel
- & Francesco Roselli
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Article
| Open AccessDecreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures
Absence seizures impair consciousness by an unknown neuronal mechanism. Here, the authors find that a rat absence seizure model’s behavior and hemodynamics recapitulate previously reported characteristics of human absence seizures, and uncover four distinct patterns of neuronal activity in cortex and thalamus during consciousness-impairing seizures.
- Cian McCafferty
- , Benjamin F. Gruenbaum
- & Hal Blumenfeld
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Article
| Open AccessCSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model
Tau-mediated neurodegeneration is driven by disease-activated microglia and suppressed by their pharmacological blockade. The authors identified drug dose- and sex-dependent residual microglial phenotypes, neuronal excitotoxicity, and animal survival.
- Noah R. Johnson
- , Peng Yuan
- & Carlo Condello
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Article
| Open AccessMolecular subtypes of ALS are associated with differences in patient prognosis
Variability in ALS disease onset and progression are poorly understood. Our work identifies three distinct molecular states in post-mortem tissue that capture some of the observed differences in patient age of onset and survival.
- Jarrett Eshima
- , Samantha A. O’Connor
- & Barbara S. Smith
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Article
| Open AccessInhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model
The study by Williams et al shows targeting the aberrant histone modifying enzyme Smyd3 rescues NMDAR and cognitive deficits in a mouse model of Alzheimer’s disease. It highlights the potential of epigenetic treatment in neurodegenerative diseases.
- Jamal B. Williams
- , Qing Cao
- & Zhen Yan
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Article
| Open AccessHuntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation
Here the authors evaluate single cell gene expression from mouse and human Huntington’s disease brains, finding incomplete oligodendrocyte maturation and pathways involved. Treating mice with thiamine/biotin ameliorates molecular pathology.
- Ryan G. Lim
- , Osama Al-Dalahmah
- & Leslie M. Thompson
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Article
| Open AccessClosed-loop direct control of seizure focus in a rodent model of temporal lobe epilepsy via localized electric fields applied sequentially
Direct stimulation of the focus of a seizure may have potential for the treatment of epilepsy. Here the authors demonstrate in a rat model a sequential narrow-field stimulation method for terminating seizures.
- Wonok Kang
- , Chanyang Ju
- & Sung-Min Park
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Article
| Open AccessExperimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae
The poor correlation between brain Aβ deposition and clinical symptoms in Alzheimer´s disease remains puzzling. Here, the authors show a temporal dissociation of Aβ deposition and neurodegeneration.
- Christine Rother
- , Ruth E. Uhlmann
- & Mathias Jucker
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Article
| Open AccessEnhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model
Mutations that enhance the activity of protein kinase C alpha (PKCα) are associated with Alzheimer’s Disease. Here, the authors report that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model.
- Gema Lordén
- , Jacob M. Wozniak
- & Alexandra C. Newton
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Article
| Open AccessPrematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS
Nuclear depletion and cytoplasmic accumulation of splicing factor SFPQ are hallmarks of ALS. Here the authors demonstrate a relationship between loss of SFPQ and the emergence in neurites of intron-retaining mRNAs enriched in ALS models and tissues.
- Richard Taylor
- , Fursham Hamid
- & Corinne Houart
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Article
| Open AccessActivated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase
Neocortical epilepsy is resistant to current treatments. Zhao et al. report that optogenetic stimulation of astrocytes effectively attenuates seizures via driving Na+-K+-ATPase, indicating a potential treatment strategy for intractable epilepsy.
- Junli Zhao
- , Jinyi Sun
- & Yi Wang
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Article
| Open AccessNorepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Sympathetic neurons are affected in familial dysautonomia, a rare disease associated with a mutation in ELP1, but the mechanisms are not fully understood. Here the authors show, using neurons derived from participants with familial dysauotnomia, that spontaneous sympathetic neuron hyperactivity is observed and is associated with norepinephrine transporter deficits.
- Hsueh-Fu Wu
- , Wenxin Yu
- & Nadja Zeltner
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