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Article
| Open AccessAltered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease
Succinylation is a metabolism-associated post-translational protein modification. Here the authors describe changes to the succinylation of proteins in the brain of individuals with Alzheimer’s disease.
- Yun Yang
- , Victor Tapias
- & Gary E. Gibson
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Article
| Open AccessReactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Alzheimer’s disease is associated with changes in astrocytes. Here the authors investigated the astrocyte translatome associated with amyloid-ß and tau pathology.
- Zoeb Jiwaji
- , Sachin S. Tiwari
- & Giles E. Hardingham
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Article
| Open AccessModulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations
Dopamine tone modulation generates changes in beta oscillation physiology. Here the authors show beta frequency, and not power, coherence, phase-locking, or PAC is monotonically linked to dopamine tone and is likely the key property of pathological oscillations in cortical and basal ganglia networks.
- L. Iskhakova
- , P. Rappel
- & H. Bergman
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Article
| Open AccessAtlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue
Resources reporting RNA editing sites from brain tissue have been published. Here, the authors provide an atlas of RNA editing events found in the aged and Alzheimer’s disease human brain tissue resulting in changes at protein level.
- Yiyi Ma
- , Eric B. Dammer
- & Philip L. De Jager
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Article
| Open AccessStroke subtype-dependent synapse elimination by reactive gliosis in mice
Microglia and astrocytes clear neuronal debris after stroke, whether glia remain phagocytic and cause synapse loss at the subacute stage remains unknown. Here, the authors show in a murine model of ischemic stroke that inhibition of phagocytosis by MEGF10 and MERTK deletion in microglia and astrocytes attenuated damage and improved neurological outcomes by preventing synapse loss.
- Xiaojing Shi
- , Longlong Luo
- & Guo-Yuan Yang
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Article
| Open AccessFat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice
Post-transcriptional modification of RNA can contribute to regulating behavior. Here, the authors show that modulating the expression of Fto results in epitranscriptomic changes in the mouse hippocampus associated with depression-like behavior.
- Shu Liu
- , Jianbo Xiu
- & Qi Xu
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Article
| Open AccessAxonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins
Here, the authors show in human iPSC-derived motor neurons from ALS patients and a TDP-43 mouse model that axonal TDP-43 forms G3BP1 positive RNP condensates, which sequester mRNA of nuclear encoded mitochondrial proteins and decrease local protein synthesis in motor neuron axons and neuromuscular junctions.
- Topaz Altman
- , Ariel Ionescu
- & Eran Perlson
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Article
| Open AccessInterrogation of the microenvironmental landscape in spinal ependymomas reveals dual functions of tumor-associated macrophages
The intratumoural heterogeneity of spinal ependymomas and the role of microglia in tumour progression remain underexplored. Here, the authors perform single-cell RNA- and ATAC-sequencing data analysis of three subtypes and reveal tumour-associated macrophage subsets with distinct functional phenotypes.
- Qianqian Zhang
- , Sijin Cheng
- & Xiaoqun Wang
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Article
| Open AccessNogoA-expressing astrocytes limit peripheral macrophage infiltration after ischemic brain injury in primates
Astrocytes are important players in ischemic stroke. Here, the authors use single nuclei transcriptomics to characterise marmoset astrocytes following brain injury. At functional level, they show that NogoAexpressing astrocytes limit macrophage infiltration.
- Anthony G. Boghdadi
- , Joshua Spurrier
- & James A. Bourne
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Article
| Open AccessDevelopmental decrease of entorhinal-hippocampal communication in immune-challenged DISC1 knockdown mice
The authors show that mice that mimic the dual genetic-environmental etiology of psychiatric risk have poor lateral entorhinal cortex-dependent recognition memory already at pre-juvenile age and abnormal communication within LECHP-PFC networks throughout development.
- Xiaxia Xu
- , Lingzhen Song
- & Ileana L. Hanganu-Opatz
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Article
| Open AccessTau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.
- Meihua Jin
- , Hiroki Shiwaku
- & Hitoshi Okazawa
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Article
| Open AccessDeficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures
ASH1L haploinsufficiency is strongly linked to autism, despite the unknown mechanism. Here, the authors show that ASH1L deficiency in prefrontal cortex causes the downregulation of synaptic genes, leading to seizures, which is rescued by chemogenetic and pharmacological restoration of excitation/inhibition balance.
- Luye Qin
- , Jamal B. Williams
- & Zhen Yan
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Article
| Open AccessNuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties
The mechanisms underlying Huntingtin protein (Htt) aggregation are not fully understood. Here the authors perform a detailed investigation of the ultrastructural and biochemical properties of huntingtin cytoplasmic and nuclear inclusions, and reveal that they form via distinct mechanisms and exert their toxicity via different pathways.
- Nathan Riguet
- , Anne-Laure Mahul-Mellier
- & Hilal A. Lashuel
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Article
| Open AccessInterferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy
Studies on interferon-driven brain pathology have so far been hampered by the lack of appropriate animal models. Here the authors characterize RNASET2-deficient mice and show that neuroinflammation and brain atrophy are IFNAR1-dependent.
- Matthias Kettwig
- , Katharina Ternka
- & Jutta Gärtner
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Article
| Open AccessDopamine D2 receptor regulates cortical synaptic pruning in rodents
Synaptic pruning is important during development and synaptic plasticity. Here, the authors show that the dopamine D2 receptor (Drd2) in the anterior cingulate cortex regulates synaptic pruning, affecting LTD and behaviour in transgenic rats.
- Ya-Qiang Zhang
- , Wei-Peng Lin
- & Dong-Min Yin
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Article
| Open AccessMicroglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
Whether microglial activation constitutes a primary pathological event in synucleinopathies is not known. Here, the authors generated a mouse model over-expressing α-synuclein in microglial cells and found these mice developed progressive dopaminergic neuron degeneration and microglia developed a reactive, pro-inflammatory state with phagocytic exhaustion.
- Simone Bido
- , Sharon Muggeo
- & Vania Broccoli
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Article
| Open AccessRepurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
Lack of expression and function of chloride ion-extruding transporter KCC2 in central neurons, a consequence of various forms of neural injury, is strongly suggested to contribute to chronic pain. Here the authors identify from a screen of cancer drugs a kinase-inhibitor, kenpaullone, as an enhancer of Kcc2/KCC2 gene expression and show that it (i) alleviates pain like behaviour in animal models, (ii) repairs neural-circuit disrupting elevated chloride in pain relay neurons in the dorsal spinal cord.
- Michele Yeo
- , Yong Chen
- & Wolfgang Liedtke
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Article
| Open AccessCDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice
Molecular mechanisms of attention-deficit hyperactivity disorder (ADHD) are not fully understood. Here the authors demonstrate a mutation in CDH2, encoding N-cadherin, that is associated with ADHD, and in a mouse model, delineate molecular electrophysiological characteristics associated with this mutation.
- D. Halperin
- , A. Stavsky
- & O. S. Birk
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Article
| Open AccessLongitudinal functional imaging of VIP interneurons reveals sup-population specific effects of stroke that are rescued with chemogenetic therapy
Stroke profoundly disrupts cortical excitability which impedes recovery, but how stroke affects inhibitory interneurons is poorly understood. Here, the authors show that functional impairments after stroke are associated with the disruption of a highly active subpopulation of interneurons expressing vasoactive intestinal peptide (VIP), which could be ameliorated by chemogenetic stimulation.
- Mohamad Motaharinia
- , Kim Gerrow
- & Craig E. Brown
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Article
| Open AccessHighly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions
Pathologic protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells via extracellular vesicles or direct cell-to-cell contact. Here, Liu et al. show that viral glycoproteins can contribute to intercellular proteopathic seed transmission via both routes.
- Shu Liu
- , André Hossinger
- & Ina M. Vorberg
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Article
| Open AccessmTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity
Autism spectrum disorder (ASD) is characterised by synaptic surplus and atypical functional connectivity. Here, the authors show that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and cortico-striatal hyperconnectivity, and that analogous functional hyperconnectivity signatures can be linked to mTOR-pathway dysfunction in subgroups of children with idiopathic ASD.
- Marco Pagani
- , Noemi Barsotti
- & Alessandro Gozzi
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Article
| Open AccessA C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation
A hexanucleotide repeat expansion of C9orf72 is translated to dipeptide repeat proteins in amyotrophic lateral sclerosis and frontotemporal dementia patients. Here the authors generate a C. elegans model of C9orf72-mediated ALS/FTD and show that translation initiation factor eIF2D regulates the dipeptide repeat protein expression.
- Yoshifumi Sonobe
- , Jihad Aburas
- & Paschalis Kratsios
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Article
| Open AccessKetamine increases activity of a fronto-striatal projection that regulates compulsive behavior in SAPAP3 knockout mice
Intravenous infusion of ketamine rapidly reduces obsessive-compulsive disorder symptoms. Here, the authors show in mice that ketamine acts by increasing activity in a fronto-striatal circuit that causally controls compulsive grooming behaviour.
- Gwynne L. Davis
- , Adelaide R. Minerva
- & Lisa A. Gunaydin
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Article
| Open AccessModeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption
Cellular models of organs have been used to investigate mechanisms of disease. Here the authors generate a human alpha synuclein-induced brain-chip model that recapitulates blood-brain barrier dysfunction, as a potential testing platform for novel therapeutics in Parkinson’s disease.
- Iosif Pediaditakis
- , Konstantia R. Kodella
- & Katia Karalis
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Article
| Open AccessInhibiting endocytosis in CGRP+ nociceptors attenuates inflammatory pain-like behavior
The authors show the endocytotic adaptor subunit called AP2A2 is differentially expressed in CGRP+ nociceptors. Locally inhibiting nociceptor endocytosis with a lipidated AP2 inhibitor peptide reduces acute and chronic pain-like behaviour in mice and rats, indicating prolonged analgesia.
- Rasheen Powell
- , Violet A. Young
- & Arin Bhattacharjee
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Article
| Open AccessAn immune response characterizes early Alzheimer’s disease pathology and subjective cognitive impairment in hydrocephalus biopsies
Specific transcriptional changes in microglia associated with Alzheimer’s disease have been reported. Here, the authors show that transcriptional analysis of human hydrocephalus biopsies identifies changes in immune response genes associated with early AD pathology, including cognitive decline.
- Wenrui Huang
- , Anne Marie Bartosch
- & Andrew F. Teich
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Article
| Open AccessMagnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice
Deep-brain stimulation ameliorates parkinsonian symptoms, but it usually requires permanent implantation of hardware and connectors. Here, the authors show magnetothermal neuromodulation through the activation of TRPV1 can improve locomotor deficits in mouse models of Parkinson’s disease.
- Sarah-Anna Hescham
- , Po-Han Chiang
- & Yasin Temel
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Article
| Open AccessPericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
Fibrotic scar tissue limits central nervous system regeneration. Here, Dias et al. show that fibrotic scarring is common in mice and humans, following distinct lesions to the adult brain and spinal cord, and derives from a discrete population of GLAST-expressing perivascular cells.
- David O. Dias
- , Jannis Kalkitsas
- & Christian Göritz
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Article
| Open AccessHecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles
Ribonucleoprotein (RNP) granules are responsible for mRNA transport and local translation required for neuronal and oocyte maturation. Here the authors show that loss of the Drosophila Ub ligase Hecw enlarges RNP granules, leads to a liquid to gel-like transition, and results in defective oogenesis and neuronal loss.
- Valentina Fajner
- , Fabio Giavazzi
- & Simona Polo
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Article
| Open AccessFunctional and molecular characterization of a non-human primate model of autism spectrum disorder shows similarity with the human disease
Non-human primate models of autism spectrum disorder (ASD) are few and not well characterised. Here, the authors describe synaptic function and gene expression changes in a marmoset model of ASD from birth to juvenile, highlighting its similarity to features observed in human ASD.
- Satoshi Watanabe
- , Tohru Kurotani
- & Noritaka Ichinohe
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Article
| Open AccessSlow update of internal representations impedes synchronization in autism
Autism is characterized by diverse symptoms, including impaired social skills, motor and perceptual atypicalities. Here, using computational modelling, the authors show that impaired synchronization ability in autism stems from reduced error correction, supporting a slow-updating account of autism.
- Gal Vishne
- , Nori Jacoby
- & Merav Ahissar
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Article
| Open AccessSelective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo
The mechanisms underlying the spreading of α-synuclein in various α-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models
- Debashis Dutta
- , Malabendu Jana
- & Kalipada Pahan
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Article
| Open AccessThe gut microbiome in konzo
Here, using metagenomic profiling in 180 individuals from the Democratic Republic of the Congo, the authors find associations between the gut microbiome and konzo, a neurodegenerative disease that mostly affects children and is caused by the consumption improperly processed cassava.
- Matthew S. Bramble
- , Neerja Vashist
- & Eric Vilain
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Article
| Open AccessSmall-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease
Mitochondrial dysfunction is a common hallmark of neurological disorders. Here, the authors identify CHIR99021 as a potent enhancer of mitochondrial function, which improved mitochondrial phenotypes in Huntington’s disease models. CHIR99021 was shown to stabilize calpastatin, which suppressed calpain activation and Drp1-induced mitochondrial fragmentation.
- Di Hu
- , Xiaoyan Sun
- & Xin Qi
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Article
| Open AccessGenetically encoded cell-death indicators (GEDI) to detect an early irreversible commitment to neurodegeneration
Cell death is a critical process in health and disease, yet available markers record later stages of cell death once a cell has already begun to decompose. Here the authors show the use of a genetically encoded calcium indicator that demarcates an irreversible stage of cell death earlier than previously possible.
- Jeremy W. Linsley
- , Kevan Shah
- & Steven Finkbeiner
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Article
| Open AccessCortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder
Mutations in CNTNAP2 have been associated with a syndromic form of Autism Spectrum Disorder. Here the authors show that forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of ASD with a homozygous truncating mutation in CNTNAP2 displayed an increase in volume and total cell number, which is driven by abnormal cellular proliferation and neurogenesis.
- Job O. de Jong
- , Ceyda Llapashtica
- & Sander Markx
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Article
| Open AccessImproved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia
Human induced pluripotent stem cell (iPSC) cells have been used to model disease in specific cell types. Here, the authors develop an automated long-term culturing platform of human iPSC neurons, astrocytes, and microglia and use it to model some cellular aspects of Alzheimer’s disease.
- Reina Bassil
- , Kenneth Shields
- & Ben Chih
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Article
| Open AccessB-SOiD, an open-source unsupervised algorithm for identification and fast prediction of behaviors
The study of naturalistic behaviour using video tracking is challenging. Here the authors develop a system, B-SOiD which allows automated behavioural tracking and segmentation of video of movements tested in mice, flies and humans.
- Alexander I. Hsu
- & Eric A. Yttri
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Article
| Open AccessNeural signatures of hyperdirect pathway activity in Parkinson’s disease
In Parkinson’s disease (PD), beta frequency oscillations are synchronised across the cortico-basal-ganglia circuit. The authors show in human participants that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway, indicating a pathophysiological role for this pathway in PD.
- Ashwini Oswal
- , Chunyan Cao
- & Vladimir Litvak
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Article
| Open AccessEpigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease
Dysfunction of the gastrointestinal system, and to the autophagy lysososmal pathway (ALP) have been reported in Parkinson’s disease. Here the authors report epigenetic disruption of ALP related genes in the appendix of individuals with Parkinson’s disease.
- Juozas Gordevicius
- , Peipei Li
- & Viviane Labrie
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Article
| Open AccessExcitatory synapses and gap junctions cooperate to improve Pv neuronal burst firing and cortical social cognition in Shank2-mutant mice
How NMDAR and GABA neuronal dysfunctions result in impaired social behaviour is unclear. Here, the authors show that NMDARs and gap junctions in cortical PV interneurons modulate burst firing, affecting social behaviour.
- Eunee Lee
- , Seungjoon Lee
- & Eunjoon Kim
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Article
| Open AccessThe paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice
Bed nucleus of the stria terminalis (BNST) neurons that synthesize and release the stress neuropeptide corticotropin-releasing factor drive binge alcohol drinking and anxiety. The authors describe a complex feedforward inhibitory PVTVGLUT2-BNSTCRF circuit in mice that plays sex-dependent roles in alcohol drinking and avoidance behavior.
- Olivia B. Levine
- , Mary Jane Skelly
- & Kristen E. Pleil
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Article
| Open AccessSumoylation regulates the assembly and activity of the SMN complex
Sumoylation is important for the assembly and function of the SMN complex, which plays a central role in RNA processing. Here the authors show that loss of this posttranslational modification impairs the ability of SMN to correct selective deficits in the sensory-motor circuit of animal models of spinal muscular atrophy.
- Giulietta M. Riboldi
- , Irene Faravelli
- & Francesco Lotti
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Article
| Open AccessNeuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior
The link between tRNA modifications, protein translation, and behavior is unclear. Here, the authors show that neuronal Nsun2 deficiency results in codon-specific epitranscriptomic changes of Gly-tRNAs and proteomic changes affecting synaptic signaling and behavior in mice.
- J. Blaze
- , A. Navickas
- & S. Akbarian
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Article
| Open AccessA common limiter circuit for opioid choice and relapse identified in a rodent addiction model
The neural circuits underlying rewarding effects of drugs of abuse and natural rewards are not fully understood. Here the authors investigate the role of the infralimbic cortex to nucleus accumbens shell pathway during heroin or food choice in rats.
- Jasper A. Heinsbroek
- , Giuseppe Giannotti
- & Jamie Peters
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Article
| Open AccessHuman sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions
Organoids have improved disease modeling. Here, the authors generate human sensorimotor organoids derived from hiPSCs of individuals with ALS. These organoids contain skeletal muscle, sensory and motor neurons as well as astrocytes, microglia, and vasculature and form neuromuscular junctions.
- João D. Pereira
- , Daniel M. DuBreuil
- & Brian J. Wainger
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Article
| Open AccessBrain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice
Chronic use of mTORC1 inhibitors produces undesirable side effects in humans which limit their value for CNS disorders treatment. The authors present a binary drug strategy to protects mTORC1 activity in the periphery and show its potential utility in preclinical models of alcohol use disorder.
- Yann Ehinger
- , Ziyang Zhang
- & Dorit Ron
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Article
| Open AccessReverse optogenetics of G protein signaling by zebrafish non-visual opsin Opn7b for synchronization of neuronal networks
Microbial rhodopsins can be used to control action potentials, while animal opsins can be used to control intracellular signaling pathways. The authors identify Opn7b as constitutively active Gi/o coupled receptor that can be deactivated by light and used to modulate neuronal activity.
- Raziye Karapinar
- , Jan Claudius Schwitalla
- & Stefan Herlitze
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Article
| Open AccessPhosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome
Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.
- Alberto Lleó
- , Henrik Zetterberg
- & Juan Fortea
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