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| Open AccessAsynchronous glutamate release is enhanced in low release efficacy synapses and dispersed across the active zone
Neurotransmitters can be released with a delay in relation to action potentials. This work demonstrates how this asynchronous release is related to overall vesicle release probability and short-term plasticity.
- Philipe R. F. Mendonça
- , Erica Tagliatti
- & Kirill E. Volynski
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Article
| Open AccessExcess ribosomal protein production unbalances translation in a model of Fragile X Syndrome
Dysregulated protein synthesis is key contributor to Fragile X syndrome. Here the authors identify a relationship between ribosome expression and the translation of long mRNAs that contributes to synaptic weakening in a model of Fragile X syndrome.
- Sang S. Seo
- , Susana R. Louros
- & Emily K. Osterweil
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| Open AccessAn in vitro model of neuronal ensembles
Advances in 3D neuronal cultures have allowed unprecedented access to the mechanisms underlying brain diseases. This work describes the novel Modular Neuronal Network (MoNNet) system, which enables more complex studies of cortical neuronal ensemble dynamics.
- M. Angeles Rabadan
- , Estanislao Daniel De La Cruz
- & Raju Tomer
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| Open AccessProteomic and functional analyses of the periodic membrane skeleton in neurons
In neurons the membrane-associated periodic skeleton (MPS) consists of actin, spectrin, and associated molecules. Here the authors use proteomic analysis and super-resolution imaging to provide insight into the molecular composition and organization of the MPS, and its functions in axon-diameter regulation and neurite-neurite interactions.
- Ruobo Zhou
- , Boran Han
- & Xiaowei Zhuang
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Article
| Open AccessDietary restriction and the transcription factor clock delay eye aging to extend lifespan in Drosophila Melanogaster
Circadian dysfunction is a potential driver of eye aging. Here the authors report that in conjunction with the core molecular clock transcription factor Clock, dietary restriction promotes rhythmic homeostatic mechanisms within photoreceptors to delay visual senescence and extend lifespan in Drosophila Melanogaster.
- Brian A. Hodge
- , Geoffrey T. Meyerhof
- & Pankaj Kapahi
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| Open AccessA synaptomic analysis reveals dopamine hub synapses in the mouse striatum
The neurotransmitter dopamine is an important regulator of brain function. Here the authors describe “dopamine hub synapses”, where dopamine transmission may act in synergy with other neurotransmitters.
- Vincent Paget-Blanc
- , Marlene E. Pfeffer
- & Etienne Herzog
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Article
| Open AccessTranscriptional adaptation of olfactory sensory neurons to GPCR identity and activity
Olfaction in mammals relies on a toolbox composed of a varied set of sensory neurons. Here, the authors report in mice that this olfactory neuronal diversity relies both on the chemoreceptor that each neuron expresses and on the experience of this neuron.
- Luis Flores Horgue
- , Alexis Assens
- & Ivan Rodriguez
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| Open AccessNeuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans
Mitochondrial deficiency causes rare incurable disorders. Here, the authors use C. elegans to study these diseases and find that the natural compound lutein prevents neurodevelopmental deficits, thus pointing to a possible therapeutic target for the human diseases.
- Silvia Maglioni
- , Alfonso Schiavi
- & Natascia Ventura
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| Open AccessKetamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice
Rawat et al. demonstrate that activation of adult-born immature hippocampal neurons is necessary and sufficient for the acute antidepressant effects of low-dose ketamine in mice.
- Radhika Rawat
- , Elif Tunc-Ozcan
- & John A. Kessler
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Article
| Open AccessLateral gain is impaired in macular degeneration and can be targeted to restore vision in mice
Treatments to rescue vision are currently limited. Here, the authors identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in humans. They also show that activating laterally projecting cells results improved vision in two mouse models of retinal degeneration.
- M. Rizzi
- , K. Powell
- & R. R. Ali
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| Open AccessLong-term in vivo imaging of mouse spinal cord through an optically cleared intervertebral window
Wu et al. developed a technique for longitudinal imaging with subcellular resolution of the spinal cord without causing inflammation or microglia activation in live mouse through an optically cleared intervertebral window.
- Wanjie Wu
- , Sicong He
- & Jianan Y. Qu
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Article
| Open AccessSWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress
Repeated exposure to social stressors in rodents results in behavioural changes. Here the authors show that behavioural adaptations to stress are associated with nuclear organization changes through SWI/SNF chromatin remodeler in specific neuronal populations of the mesolimbic system.
- Abdallah Zayed
- , Camille Baranowski
- & Sébastien Parnaudeau
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| Open AccessBrain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions
Where memories are located in our brains is not well understood. In this paper, the authors demonstrate that memories are spread out throughout multiple brain regions.
- Dheeraj S. Roy
- , Young-Gyun Park
- & Susumu Tonegawa
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| Open AccessThe Oligodendrocyte Transcription Factor 2 OLIG2 regulates transcriptional repression during myelinogenesis in rodents
Transcription factors regulate gene programs during myelination. Here, the authors show that the Oligodendrocyte Transcription Factor 2 (OLIG2) regulates the differentiation of oligodendrocyte progenitor cells into immature oligodendrocytes via SETDB1 during myelination and remyelination in rodents.
- Kunkun Zhang
- , Shaoxuan Chen
- & Wei Mo
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| Open AccessPhysiological synaptic activity and recognition memory require astroglial glutamine
The authors present a fluorescent probe that tracks glutamine in live cells. They demonstrate the capabilities of the probe by providing direct visual evidence of an activity-dependent glutamine supply from astroglial networks to presynaptic structures under physiological conditions.
- Giselle Cheung
- , Danijela Bataveljic
- & Nathalie Rouach
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| Open AccessCerebellar connectivity maps embody individual adaptive behavior in mice
The variability in synaptic connectivity observed at the cerebellar granule cell - Purkinje cell connection in mice accounts for motor behavior traits at the individual level, suggesting that cerebellar networks encode internal models underlying individual-specific motor adaptation.
- Ludovic Spaeth
- , Jyotika Bahuguna
- & Philippe Isope
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| Open AccessExpression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids
The study of human microglia function in health and disease is limited by the availability of sound models. Here, the authors develop a method to generate functional microglia in human cortical organoids and investigate the role of human microglia during amyloid beta1-42- induced inflammation.
- Bilal Cakir
- , Yoshiaki Tanaka
- & In-Hyun Park
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Article
| Open AccessMinimal genetically encoded tags for fluorescent protein labeling in living neurons
Site-specific labelling of proteins can be performed with unnatural amino acids combined with bioorthogonal click chemistry. Here the authors establish this in living neurons, using neurofilament light chain; they show combination with CRISPR/Cas9 engineering to tag the endogenous protein.
- Aleksandra Arsić
- , Cathleen Hagemann
- & Ivana Nikić-Spiegel
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| Open AccessSingle-cell transcriptomics captures features of human midbrain development and dopamine neuron diversity in brain organoids
3D brain organoids have been used to investigate human brain development and pathology. Here the authors establish human ventral midbrain organoids coupled with single cell sequencing to study developing and mature dopamine neurons and use silk scaffolding to generate bioengineered brain organoids
- Alessandro Fiorenzano
- , Edoardo Sozzi
- & Malin Parmar
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Article
| Open AccessExtracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R
Synapses are surrounded by an extracellular matrix (ECM) of extremely long-lived proteins that is thought to only be remodeled by proteolysis and de novo synthesis. Here, the authors show an alternative molecular recycling mechanism that occurs for the key ECM protein Tenascin-R.
- Tal M. Dankovich
- , Rahul Kaushik
- & Silvio O. Rizzoli
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| Open AccessAn injury-induced serotonergic neuron subpopulation contributes to axon regrowth and function restoration after spinal cord injury in zebrafish
The mechanisms involved in regeneration of the spinal cord after injury are unclear. Here, the authors show that a subpopulation of intraspinal serotonergic neurons localized at the injury site stimulates axonal regrowth of interneurons via 5-HT1B receptor, resulting in recovery of function following SCI in zebrafish.
- Chun-Xiao Huang
- , Yacong Zhao
- & Jianren Song
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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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| 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 AccessBioorthogonal labeling of transmembrane proteins with non-canonical amino acids unveils masked epitopes in live neurons
Visualisation of TARP localisation is hindered by existing imaging tools. Here the authors report a labelling and imaging platform using genetic code expansion and non-canonical amino acids; they use this to fluorescently label live neurons and localise TARP proteins using super resolution microscopy.
- Diogo Bessa-Neto
- , Gerti Beliu
- & Daniel Choquet
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| 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 AccessDrosophila ßHeavy-Spectrin is required in polarized ensheathing glia that form a diffusion-barrier around the neuropil
In the invertebrate CNS, synapses and dendrites are clustered in distinct neuropil areas that are separated from neuronal cell bodies by ensheathing glia (EG). Here, the authors show that Drosophila EG are polarized cells that form an internal diffusion barrier. EG cell polarity requires βHeavy-Spectrin and is needed for normal locomotor behaviour.
- Nicole Pogodalla
- , Holger Kranenburg
- & Christian Klämbt
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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 AccessGraded heterogeneity of metabotropic signaling underlies a continuum of cell-intrinsic temporal responses in unipolar brush cells
The authors show that graded molecular heterogeneity in metabotropic pathways underlies a continuum of temporal responses in cerebellar unipolar brush cells (UBCs). This allows the UBC population to serve as a cell-autonomous basis for temporal integration and learning over multiple time scales.
- Chong Guo
- , Vincent Huson
- & Wade G. Regehr
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Article
| Open AccessCircadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids
It is unclear how circadian signals from the suprachiasmatic nucleus (SCN) are decoded to generate daily rhythms in hormone release. Here, the authors show that daily corticosterone release depends on coordinated clock gene and neuronal activity rhythms in both SCN and paraventricular nucleus neurons.
- Jeff R. Jones
- , Sneha Chaturvedi
- & Erik D. Herzog
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| Open AccessA harmonized atlas of mouse spinal cord cell types and their spatial organization
Single-cell profiling has led to the identification of diverse cell types. Here, the authors generate a harmonized cell atlas of the mouse post-natal spinal cord. They also provide spatial analysis of the distribution of the identified cell types and an open-source cell type classifier.
- Daniel E. Russ
- , Ryan B. Patterson Cross
- & Ariel J. Levine
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Article
| Open AccessAcetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits
In this study, acetylcholine release is shown to reorganise hippocampal CA1 inhibitory networks resulting in prioritisation of entorhinal input over CA3 input. This is achieved by activation of a combination of M3 and M4 muscarinic receptors.
- Jon Palacios-Filardo
- , Matt Udakis
- & Jack R. Mellor
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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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| Open AccessER – lysosome contacts at a pre-axonal region regulate axonal lysosome availability
In neurons and other cells, contacts between organelles regulates function and subcellular organization, but the precise mechanisms and effects are unclear. Here the authors show that endoplasmic reticulum (ER) tubules in the soma of neurons regulate lysosome localization and function by regulating lysosomal fission, suggesting a role for ER – lysosome inter-organelle membrane contact sites in lysosomal axonal availability.
- Nazmiye Özkan
- , Max Koppers
- & Ginny G. Farías
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Article
| Open AccessAuditory input enhances somatosensory encoding and tactile goal-directed behavior
Multi-sensory input can lead to dendritic integration at the single neuron level. Here the authors show that combined auditory and somatosensory input increases distal dendritic and somatic activity in layer 2/3 pyramidal neurons of the primary somatosensory cortex and decreases response latency during somatosensory-based goal-directed behaviour.
- L. Godenzini
- , D. Alwis
- & L. M. Palmer
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Article
| Open AccessMiniature neurotransmission is required to maintain Drosophila synaptic structures during ageing
Synaptic structures disintegrate and fragment as ageing progresses. Here the authors find that miniature neurotransmission is required to maintain adult motor synapse structures in Drosophila and that increasing miniature events can preserve motor ability during ageing.
- Soumya Banerjee
- , Samuel Vernon
- & Brian D. McCabe
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Article
| Open AccessExtensive transcriptional and chromatin changes underlie astrocyte maturation in vivo and in culture
Astrocytes have functions crucial for brain homeostasis, which are disrupted in many neurological disorders, but how these functions are established during astrocyte maturation is largely unknown. Here the authors show transcriptional and chromatin changes underlying astrocyte maturation in mice and identify transcription factors regulating maturation of cultured astrocytes.
- Michael Lattke
- , Robert Goldstone
- & Francois Guillemot
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Article
| Open AccessPurkinje cell axonal swellings enhance action potential fidelity and cerebellar function
Axonal swellings have been found on Purkinje cell axons in the cerebellum both during development and disease. The authors show that axons with swellings propagate action potentials with higher fidelity than those without and that mice with more axonal swellings learn cerebellar-related tasks better.
- Daneck Lang-Ouellette
- , Kim M. Gruver
- & Alanna J. Watt
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| Open AccessLong noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons
Long noncoding RNAs (lncRNAs) are known to regulate the DNA damage response (DDR), however their role in the brain is less well studied. Here, the authors demonstrate a neuron-specific role for Brain Specific DNA-damage Related lncRNA1 (BS-DRL1) and show BS-DRL1 modulates DDR by interacting with HMGB1 in a cell-type specific manner.
- Min-Min Lou
- , Xiao-Qiang Tang
- & Wen-Yuan Wang
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Article
| Open AccessThe Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
The Atr-Check1 pathway is involved in cell cycle and the DNA damage response. Here, the authors show that the Atr-Check1 pathway can inhibit axon regeneration in response to Piezo-mediated mechanosensation, affecting functional recovery.
- Feng Li
- , Tsz Y. Lo
- & Yuanquan Song
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Article
| Open AccessPKC-phosphorylation of Liprin-α3 triggers phase separation and controls presynaptic active zone structure
Liquid–liquid phase separation may be a mechanism for organizing the presynaptic nerve terminal. Here, the authors show that PKC-mediated phosphorylation of Liprin-α3 triggers phase separation in cell lines and modulates active zone structure and function in primary hippocampal neurons.
- Javier Emperador-Melero
- , Man Yan Wong
- & Pascal S. Kaeser
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Article
| Open AccessTranssynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses
Post‐tetanic potentiation (PTP) is a major form of plasticity at hippocampal mossy fiber synapses and is considered an entirely presynaptic phenomenon. The authors show that mossy fiber PTP not only lacks associativity, but rather shows anti‐associative induction properties, implementing a brake on mossy fiber detonation.
- David Vandael
- , Yuji Okamoto
- & Peter Jonas
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Article
| Open AccessTanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons
Alterations of the mTOR signalling pathway are associated with neurodevelopmental defects. Regulators of the mTOR kinase activity are not fully described. Here, the authors show that Tanc2, a scaffolding protein, acts as a direct inhibitor of mTOR kinase activity in the developing mouse brain and cultured human neurons.
- Sun-Gyun Kim
- , Suho Lee
- & Eunjoon Kim
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Article
| Open AccessDiversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences
The unique biophysical properties of human cortical neurons that may underlie interlaminar communication are explored. With a focus on Ih and layers 2&3, 3c, and 5, the authors show that L5 pyramidal neurons are better adapted than their superficial layer counterparts to track delta and theta frequency inputs.
- Homeira Moradi Chameh
- , Scott Rich
- & Taufik A. Valiante
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Article
| Open AccessSingle nucleus RNA-sequencing defines unexpected diversity of cholinergic neuron types in the adult mouse spinal cord
The full heterogeneity and different functional roles of cholinergic neurons in the adult spinal cord remain to be defined. Here the authors develop a targeted single nuclear RNA sequencing approach and use it to identify an array of cholinergic interneurons, as well as visceral and skeletal motor neurons.
- Mor R. Alkaslasi
- , Zoe E. Piccus
- & Claire E. Le Pichon
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Article
| Open AccessSight of parasitoid wasps accelerates sexual behavior and upregulates a micropeptide gene in Drosophila
Parasitoids exploit host bodies for reproduction, selecting for host defences. A new host defence is reported, in which adult Drosophila accelerate mating behaviour at the sight of certain parasitoid wasps, mediated by the upregulation of a nervous system gene that encodes a 41-amino acid micropeptide.
- Shimaa A. M. Ebrahim
- , Gaëlle J. S. Talross
- & John R. Carlson
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Article
| Open AccessTranscriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease
Alzheimer’s disease (AD) is typically associated with hippocampal and cortical pathology, although hippocampal sparing and limbic predominant forms exist. The authors use transcriptomic analysis and neuropathology to identify genes associated with selective hippocampal vulnerability in AD.
- Angela M. Crist
- , Kelly M. Hinkle
- & Melissa E. Murray
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Article
| Open AccessHypothalamic Rax+ tanycytes contribute to tissue repair and tumorigenesis upon oncogene activation in mice
Tanycytes contribute to the regulation of multiple hypothalamic functions. Here the authors investigate the regenerative and tumorigenic potential of adult Rax+ tanycytes in the median eminence in the context of the stem cell niche in mice.
- Wenhui Mu
- , Si Li
- & Qing-Feng Wu
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Article
| Open AccessAcetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
The tau protein has been implicated in neurodegenerative disorders and can propagate from cell to cell. Here, the authors show that tau acetylation reduces its degradation by chaperone-mediated autophagy, causing re-routing to other autophagic pathways and increasing extracellular tau release.
- Benjamin Caballero
- , Mathieu Bourdenx
- & Ana Maria Cuervo
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Article
| Open AccessATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking
The molecular mechanisms mediating nociception are unclear. Here, the authors show that the Activating Transcription Factor 4 (ATF4) is important for the response to heat nociception in mice and ATF4 role in mediating protein trafficking in dorsal root ganglion neurons.
- Man-Xiu Xie
- , Xian-Ying Cao
- & Xiao-Long Zhang