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| Open AccessAlkyne-tagged SERS nanoprobe for understanding Cu+ and Cu2+ conversion in cuproptosis processes
Simultaneously quantifying mitochondrial Cu+ and Cu2+ levels is vital for understanding the molecular mechanism of mitochondria-related biological events. Here the authors report an alkynyl-labeled SERS probe to simultaneously monitor free Cu+ and Cu2+ in mitochondria, and unveil their roles during ischemia and cuproptosis processes.
- Sihan Zhang
- , Yuxiao Mei
- & Yang Tian
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Article
| Open AccessIntercellular communication atlas reveals Oprm1 as a neuroprotective factor for retinal ganglion cells
How the neighboring cells contribute to the survival and functions of neuronal cells remains elusive. Here, authors identified the cell-cell interactions between retinal ganglion cells (RGCs) and other cells after RGC injury and discovered the μ-opioid receptor promotes RGC resilience.
- Cheng Qian
- , Ying Xin
- & Jiang Qian
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Article
| Open AccessDeath Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging
Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.
- Bidur Paudel
- , Si-Yeon Jeong
- & Marcus E. Peter
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| Open Accessα-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice
α-Synuclein aggregates in Lewy bodies (LBs) have not been widely used for research due to the limited availability of diseased brains. Here, the authors report a mouse model that recapitulates LB diseases using the LB amplification method.
- Norihito Uemura
- , Nicholas P. Marotta
- & Virginia M.-Y. Lee
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| Open AccessNPC1-dependent alterations in KV2.1–CaV1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease
The molecular mechanisms connecting Niemann Pick C1 cholesterol transporter (NPC1) loss to Niemann-Pick Type C neuropathology remain unknown. Here, the authors demonstrate that loss of NPC1 function alters the nanoscale distribution and function of ion channels to promote abnormal calcium entry, mitochondrial dysfunction, and neurotoxicity.
- Maria Casas
- , Karl D. Murray
- & Eamonn J. Dickson
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Article
| Open AccessAn optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models
An optimized agonist of Nurr1, 4A7C-301, protects dopamine neurons against environmental and genetic risk factors of Parkinson’s disease (PD) in vitro, and improves both motor and non-motor deficits in male rodent models of PD.
- Woori Kim
- , Mohit Tripathi
- & Kwang-Soo Kim
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Article
| Open AccessLC3-associated phagocytosis promotes glial degradation of axon debris after injury in Drosophila models
Glia are housekeepers of the nervous system that eliminate neuronal debris after injury. Here, the authors show that LC3-associated phagocytosis in Drosophila glia promotes debris clearance after wing nerve injury and recovery after traumatic brain injury.
- Áron Szabó
- , Virág Vincze
- & Gábor Juhász
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| Open AccessA pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides
Parkinson’s disease (PD) is linked to environmental factors. Through quantitative epidemiology, this study ties 53 pesticides to PD. An innovative human stem cell platform revealed that 10 of these were directly toxic to human dopamine neurons.
- Kimberly C. Paul
- , Richard C. Krolewski
- & Beate Ritz
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| 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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| 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 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 AccessHydrogel oxygen reservoirs increase functional integration of neural stem cell grafts by meeting metabolic demands
Injectable biomimetic hydrogels hold significant promise for tissue engineering applications. Here, the authors present a hybrid myoglobin:peptide hydrogel to overcome a critical oxygen shortage following neural stem cell transplantation, thus increasing cell survival and integration.
- Y. Wang
- , E. R. Zoneff
- & D. R. Nisbet
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Article
| Open AccessCiliary neurotrophic factor-mediated neuroprotection involves enhanced glycolysis and anabolism in degenerating mouse retinas
Rhee et al. demonstrates that the potent neuroprotective agent CNTF significantly impacts metabolism of degenerating retinas, thus revealing cellular mechanisms underlying enhanced neuronal viability and providing insight for the ongoing CNTF clinical trials.
- Kun Do Rhee
- , Yanjie Wang
- & Xian-Jie Yang
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Article
| Open AccessINF2-mediated actin filament reorganization confers intrinsic resilience to neuronal ischemic injury
Post injury cytoskeletal modifications in neurons are not fully understood. Here the authors describe a pro-survival actin cytoskeletal reorganization in neurons triggered during a model of ischemic stroke.
- Barbara Calabrese
- , Steven L. Jones
- & Shelley Halpain
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| Open AccessRETRACTED ARTICLE: Pharmacological perturbation of CXCL1 signaling alleviates neuropathogenesis in a model of HEVA71 infection
Neurological complications are frequently observed in severe Hand, Foot and Mouth Disease but the underlying causes are unknown. Here, the authors report infected astrocytes release CXCL1 which activates neuronal CXCR2 to cause neuropathogenesis.
- Saravanan Gunaseelan
- , Mohammed Zacky Ariffin
- & John Jia En Chua
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Article
| Open AccessUBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.
- Manivannan Subramanian
- , Seung Jae Hyeon
- & Kweon Yu
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Article
| Open AccessLongitudinal in vivo imaging of acute neuropathology in a monkey model of Ebola virus infection
The neurological effects of Ebola disease in the acute stage are not well-described. Here, the authors use longitudinal in vivo neuroimaging and immunohistochemistry to assess pathological changes in the central nervous system in a non-human primate model of Ebola virus infection.
- William Schreiber-Stainthorp
- , Jeffrey Solomon
- & Dima A. Hammoud
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Article
| Open AccessABHD4-dependent developmental anoikis safeguards the embryonic brain
During embryonic development, neural progenitor cells undergo numerous cell divisions. Here, the authors show that ABHD4-mediated developmental anoikis distinguishes the physiological delamination and the pathological detachment of progenitor cells with relevance to fetal alcohol-induced apoptosis.
- Zsófia I. László
- , Zsolt Lele
- & István Katona
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Article
| Open AccessPolyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
Small molecule polyamines participate in diverse aspects of cell growth and differentiation and are known to regulate ion channel gating. Here authors reveal that cellular polyamines control nicotinic acetylcholine receptor (nAChR) biogenesis, and either catabolic degradation or inhibition of polyamine production augments nAChR assembly.
- Madhurima Dhara
- , Jose A. Matta
- & David S. Bredt
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Article
| Open AccessIncreased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral β-amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular Aβ oligomers and the mitochondrial calcium uniporter.
- Maria Calvo-Rodriguez
- , Steven S. Hou
- & Brian J. Bacskai
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Article
| Open AccessDeletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
Topoisomerase 1 (TOP1) relieves DNA torsional stress during transcription and facilitates the expression of long neuronal genes. Here we show that deletion of Top1 in excitatory neurons leads to early onset neurodegeneration that is partially dependent on p53/PARP1 activation and NAD+ depletion.
- Giulia Fragola
- , Angela M. Mabb
- & Mark J. Zylka
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Article
| Open AccessCav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
Voltage-gated Ca2+ channels are thought to contribute to neurodegeneration of dopaminergic neurons. Here the authors find that the R-type channel Cav2.3 in substantia nigra dopaminergic neurons may contribute to neurodegeneration in a model of Parkinson’s disease, in contrast to the neuroprotective action of the neuronal Ca2+ sensor NCS-1.
- Julia Benkert
- , Simon Hess
- & Birgit Liss
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Article
| Open AccessDevelopmental cell death regulates lineage-related interneuron-oligodendroglia functional clusters and oligodendrocyte homeostasis
During cortical development the first wave of oligodendrocyte precursor cells (OPCs) completely disappear by programmed cell death, so that it is presumed that this OPC population does not play a role at postnatal stages. In this study, authors use lineage tracing in different transgenic mice to show that a subpopulation of OPCs from the first wave survives at postnatal stages and display a preferential synaptic connectivity with their ontogenetically-related interneurons compared to other OPCs or interneurons
- David Orduz
- , Najate Benamer
- & María Cecilia Angulo
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Article
| Open AccessTau binding protein CAPON induces tau aggregation and neurodegeneration
To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, the authors screened for tau-interacting proteins. They demonstrated that a novel tau binding protein CAPON accelerates tau pathology and neuronal cell death in an Alzheimer’s disease mouse model.
- Shoko Hashimoto
- , Yukio Matsuba
- & Takashi Saito
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Article
| Open AccessBrain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
It is unclear if neuromelanin plays a role in Parkinson’s disease pathogenesis since common laboratory animals lack this pigment. Authors show here that overexpression of human tyrosinase in the substantia nigra of rats resulted in an age-dependent production of human-like neuromelanin within nigral dopaminergic neurons and is associated with a Parkinson’s disease phenotype when allowed to accumulate above a specific threshold.
- Iria Carballo-Carbajal
- , Ariadna Laguna
- & Miquel Vila
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Article
| Open AccessMutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis
Impairment of DNA repair has been associated with neurodegeneration. Here the authors investigate the mechanisms of defects in repair caused by mutations in the RNA/DNA binding protein FUS in amyotrophic lateral sclerosis and elucidate its role in the DNA ligation during DNA single-strand break repair of oxidative breaks.
- Haibo Wang
- , Wenting Guo
- & Muralidhar L. Hegde
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Article
| Open AccessExcitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1
Excitotoxicity due to excessive glutamate release causes oxidative stress and neuronal death, and is a feature of many brain diseases. Here the authors show that protein kinase D1 is inactivated by excitotoxicity in a model of stroke and that its activation can be neuroprotective.
- Julia Pose-Utrilla
- , Lucía García-Guerra
- & Teresa Iglesias
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Article
| Open AccessTau exacerbates excitotoxic brain damage in an animal model of stroke
Excitotoxicity contributes to neuronal injury following stroke. Here the authors show that tau promotes excitotoxicity by a post-synaptic mechanism, involving site-specific control of ERK activation, in a mouse model of stroke.
- Mian Bi
- , Amadeus Gladbach
- & Lars M. Ittner
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Article
| Open AccessIntestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila
Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer’s disease.
- Shih-Cheng Wu
- , Zih-Syuan Cao
- & Jyh-Lyh Juang
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Article
| Open AccessTargeted two-photon chemical apoptotic ablation of defined cell types in vivo
Investigating cell death in living organisms is hampered by a lack of techniques to induce apoptosis with spatial and temporal precision without collateral damage. Here the authors develop two-photon chemical apoptotic targeted ablation (2Phatal), allowing studies of apoptosis and its functional consequencesin vivo.
- Robert A. Hill
- , Eyiyemisi C. Damisah
- & Jaime Grutzendler
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| Open AccessLoss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity
Mutations inCHCHD10 have been recently associated with frontotemporal dementia and amyotrophic lateral sclerosis. Here the authors study the functions of endogenous CHCHD10 in Caenorhabditis elegans, primary neurons, and mouse, and show that it normally protects mitochondria and synaptic integrity, and retains TDP-43 in the nucleus.
- Jung-A. A. Woo
- , Tian Liu
- & David E. Kang
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Article
| Open AccessLinear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis
Mutations in optineurin are associated with neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, the authors report the structure of the ubiquitin binding domain of optineurin, which binds linear ubiquitin with homology to NEMO, and explore the function of this domain.
- Seshiru Nakazawa
- , Daisuke Oikawa
- & Fuminori Tokunaga
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Article
| Open AccessNitric oxide mediates glial-induced neurodegeneration in Alexander disease
Alexander disease is a rare neurological disorder caused by mutations in GFAP, yet it is unclear how glial disruptions lead to neural death. Here, Wang et al. identify a mechanism by which glial-derived nitric oxide leads to neuronal degeneration in fly and mouse models of the disease.
- Liqun Wang
- , Tracy L. Hagemann
- & Mel B. Feany
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The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity
TAR DNA-binding protein of 43 kDa (TDP-43) and its C-terminal fragment of 25 kDa (CTF25) play critical roles in several neurodegenerative diseases but the cleavage site that generates CTF25 remains undetermined. Here the authors show that caspase-4 cleaves TDP-43 after Aps174 generating CTF25, and this leads to TDP-43 clearance and increased cell viability.
- Quan Li
- , Moe Yokoshi
- & Yukio Kawahara
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Receptor-interacting protein 140 attenuates endoplasmic reticulum stress in neurons and protects against cell death
Uncontrolled calcium release from the endoplasmic reticulum results in cell death and toxicity. Here, the authors show that in neurons, stress induces the export of receptor-interacting protein 140 from the nucleus to the cytosol where it interacts with IP3Receptor, preventing its opening and the detrimental effects of calcium release.
- Xudong Feng
- , Kelly A. Krogh
- & Li-Na Wei
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Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia
The removal of dying neurons by microglia plays a key role in both vertebrate nervous system development and several diseases. Here, the authors use a quantitative live imaging approach to investigate neuronal-microglial interactions at single-cell resolution and establish the functions of the phosphatidylserine receptors, TIM-4 and BAI1, in neuronal engulfment.
- Fargol Mazaheri
- , Oksana Breus
- & Francesca Peri
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The APC/C cofactor Cdh1 prevents replicative stress and p53-dependent cell death in neural progenitors
The E3-ubiquitin ligase APC/C and its cofactor Cdh1 have been shown to play important roles in axonal growth and synaptic plasticity. In this study, Eguren et al.show that elimination of Cdh1 in the developing nervous system results in defects in the neural progenitor compartment, hydrocephalus and reduced lifespan.
- Manuel Eguren
- , Eva Porlan
- & Marcos Malumbres