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| Open AccessEngineering of a bona fide light-operated calcium channel
Existing optogenetic methods to induce calcium mobilisation lack selectivity and specificity. Here, the authors design and engineer a single-component light-operated calcium channel to provide optical control over calcium signals and calcium-dependent physiological responses: LOCa.
- Lian He
- , Liuqing Wang
- & Yubin Zhou
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Article
| Open AccessSmall molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model
Synthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here the authors show the mechanism by which a small molecule targets the disease-causing r(UGGAA)n repeat RNAs in spinocerebellar ataxia type 31.
- Tomonori Shibata
- , Konami Nagano
- & Kazuhiko Nakatani
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Article
| Open AccessFilamentous recombinant human Tau activates primary astrocytes via an integrin receptor complex
The mechanisms underlying the transmission of Tau in astrocytes are unclear. Here, the authors show that the entry of filamentous recombinant human Tau into astrocytes via the integrin αV/ β1 complex stimulates integrin signaling, resulting in activation of NFκB and astrocyte conversion towards a neurotoxic state.
- Peng Wang
- & Yihong Ye
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Article
| Open AccessConcordant peripheral lipidome signatures in two large clinical studies of Alzheimer’s disease
The onset and pathology of Alzheimer’s disease (AD) is associated with changes to lipid metabolism. Here, the authors analysed 569 lipids from 32 classes and subclasses in two independent patient cohorts to identify key lipid pathways to link the plasma lipidome with AD and the future onset of AD.
- Kevin Huynh
- , Wei Ling Florence Lim
- & Peter J. Meikle
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Article
| Open AccessAssociation of APOE e2 genotype with Alzheimer’s and non-Alzheimer’s neurodegenerative pathologies
The apolipoprotein E (APOE) gene contains both the major common risk variant associated with clinically diagnosed late onset Alzheimer’s disease (AD), APOE e4, and a neuroprotective variant, APOE e2. Here the authors confirm that the e2 allele is protective against Alzheimer’s disease neuropathologies, but show that it is not protective against other neurodegenerative disorders.
- Terry E. Goldberg
- , Edward D. Huey
- & D. P. Devanand
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Article
| Open AccessNEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease
Defective protein quality control is a key feature of neurodegeneration. Here, the authors show that mutations in Nemf/NEMF, a component of the Ribosome-associated Quality Control complex, have a neurodegenerative effect in mice and may underlie neuromuscular disease in seven unrelated families.
- Paige B. Martin
- , Yu Kigoshi-Tansho
- & Gregory A. Cox
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Article
| Open AccessProtrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation
Interorganelle membrane contact sites between the endoplasmic reticulum and the endolysosome. Here, the authors show that ER-endolysosome membrane contact sites are promoted by the proteins protrudin and PDZD8 and may contribute to lipid extraction at these contact sites.
- Michiko Shirane
- , Mariko Wada
- & Keiichi I. Nakayama
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Article
| Open AccessPharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain
Blood–brain barrier dysfunction occurs in ageing and in neurodegenerative diseases. Here, the authors use scRNA-seq to identify transcriptomic changes in endothelial cell subtypes in the aged mouse brain, some of which may generalize to human and can be reversed by treatment with a GLP-1R agonist.
- Lei Zhao
- , Zhongqi Li
- & Ho Ko
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Article
| Open AccessFrataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons
Friedreich’s ataxia (FRDA) is an autosomal-recessive disorder. Here the authors describe a DRG organoid from patient derived-neurons and co-culture with muscle cells to mimic the disorder in vitro and demonstrate potential correction of the phenotype by CRISPR based editing.
- Pietro Giuseppe Mazzara
- , Sharon Muggeo
- & Vania Broccoli
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Article
| Open AccessSynucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling
The nanoscale organisation of the brain extracellular space can be studied in vivo. Here, the authors investigate how it changes in response to α-synuclein pathology, and identify interactions between microglia and the extracellular matrix.
- Federico N. Soria
- , Chiara Paviolo
- & Erwan Bezard
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Article
| Open AccessC9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression
C9orf72 repeat expansion is the major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, the authors show that transcriptome aberrations commonly found in c9ALS/FTD are a result from defects in cellular RNA surveillance pathways that involve an RNA helicase UPF1.
- Yu Sun
- , Aziz Eshov
- & Junjie U. Guo
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Article
| Open AccessComprehensive identification of mRNA isoforms reveals the diversity of neural cell-surface molecules with roles in retinal development and disease
Here the authors present an approach that can reveal the full complement of mRNA isoforms encoded by individual genes, and they identify a major isoform of the retinal degeneration gene CRB1 which functions at the cell-cell junctions of the outer limiting membrane to promote photoreceptor survival.
- Thomas A. Ray
- , Kelly Cochran
- & Jeremy N. Kay
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Article
| Open AccessProlonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons
Disruption of autophagy function in cellular and animal models of tauopathy increases tau aggregation. Here, the authors describe a small-molecule screen to identify compounds that promote autophagy clearance of tau and rescue disease-relevant phenotypes in tauopathy patient-derived neurons.
- M. Catarina Silva
- , Ghata A. Nandi
- & Stephen J. Haggarty
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Article
| Open AccessHDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease
Defects in DNA repair have been linked to brain aging and neurodegenerative disorders. Here the authors reveal a role for HDAC1 in stimulating OGG1 activity to alleviate 8-oxoG lesions with implications in the aging brain and neurodegenerative diseases.
- Ping-Chieh Pao
- , Debasis Patnaik
- & Li-Huei Tsai
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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 AccessOptogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons
Optogenetic approaches for inducing TDP-43 aggregation have been described previously in cellular models. Here the authors develop an approach to optogenetically induce TDP-43 aggregation in vivo using zebrafish to model ALS pathologies.
- Kazuhide Asakawa
- , Hiroshi Handa
- & Koichi Kawakami
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Article
| Open AccessAutonomic ganglionic injection of α-synuclein fibrils as a model of pure autonomic failure α-synucleinopathy
Autonomic dysfunction is a feature of some α-synucleinopathies, but there are no models of pure autonomic dysfunction associated with α-synuclein. Here the authors describe a mouse model of pure autonomic dysfunction without motor dysfunciton by injection of pre-formed fibrils of α-synuclein to the stellate and celiac ganglia.
- Xue-Jing Wang
- , Ming-Ming Ma
- & Xue-Bing Ding
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Article
| Open AccessTransmission of tauopathy strains is independent of their isoform composition
Although normal human brains express 6 tau isoforms in equal ratio with 3 or 4 microtubule-binding repeat domains (3R and 4R), tau inclusions from different human tauopathy brains, now considered as different strains, have distinct isoform compositions and strain properties and the relationship between these two parts is unclear. Here the authors generate a new transgenic mouse line expressing 6 human tau isoforms with equal 3R and 4R ratios, recapitulate distinct human tau strains in mouse brains with similar isoform compositions and cell type specificities, and further show the strain transmission pattern is independent of its isoform composition.
- Zhuohao He
- , Jennifer D. McBride
- & Virginia M. -Y. Lee
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Article
| Open AccessTranscription elongation factor AFF2/FMR2 regulates expression of expanded GGGGCC repeat-containing C9ORF72 allele in ALS/FTD
Mechanisms of transcription of expanded G4C2 repeats in C9ORF72, associated with ALS/FTD, are not fully understood. Here authors use both Drosophila and C9ORF72 iPSC-derived neurons and identify AFF2/FMR2 as a regulator of poly(GR) toxicity by regulating expression of the expanded G4C2 repeats.
- Yeliz Yuva-Aydemir
- , Sandra Almeida
- & Fen-Biao Gao
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Article
| Open AccessConstitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau
Accumulation of abnormal tau protein drives neurodegeneration in Alzheimer’s disease and related dementia disorders. Here, the authors demonstrate the endoplasmic reticulum unfolded protein response mediator XBP-1 controls pathological tau accumulation and the resultant neurodegeneration in a transgenic C. elegans model.
- Sarah M. Waldherr
- , Timothy J. Strovas
- & Brian C. Kraemer
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Article
| Open AccessThe mutational landscape of a prion-like domain
TDP43 aggregates are a hallmark of amyotrophic lateral sclerosis. By using deep mutagenesis to measure the toxicity of more than 50,000 mutations in the prion domain of TDP43, the authors conclude that mutations that increase toxicity promote formation of liquid-like condensates, while aggregation of TDP43 is protective for the cell.
- Benedetta Bolognesi
- , Andre J. Faure
- & Ben Lehner
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Article
| Open AccessDifferentiation but not ALS mutations in FUS rewires motor neuron metabolism
While energy metabolism has been repeatedly linked to ALS, motor neuron metabolism remains poorly studied. Here, authors show that human iPSCs rewire specific metabolic routes when they differentiate into functional motor neurons and that ALS-causing mutations in FUS do not affect energy metabolism.
- Tijs Vandoorne
- , Koen Veys
- & Ludo Van Den Bosch
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Article
| Open AccessGalectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease
The authors show that Galectin-3 is up–regulated in brain tissues from patients and a mouse model of Huntington’s disease (HD) and correlates with disease severity. Galectin-3 accumulates at damaged lysosomes in HD microglia, prevents the clearance of damaged lysosomes, and promotes inflammation.
- Jian Jing Siew
- , Hui-Mei Chen
- & Yijuang Chern
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Article
| Open AccessProduction of seedable Amyloid-β peptides in model of prion diseases upon PrPSc-induced PDK1 overactivation
Aβ plaques have been detected in brains of patients with prion diseases. Here, using mice, the authors show that prion infection enhances Aβ production via a PDK1-TACE mechanism and that brain deposition of Aβ induced by Aβ seeds co-transmitted with PrPSc contributes to mortality in prion disease.
- Juliette Ezpeleta
- , Vincent Baudouin
- & Benoit Schneider
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Article
| Open AccessMotor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR
Repeat-associated non-ATG translation of dipeptide repeat proteins (DPRs) contributes to disease manifestation in FTD/ALS associated with the hexanucleotide repeat expansion of the C9ORF72 gene. Here the authors show that a transgenic mouse line expressing poly-PR28 in neurons displays some signs of neuronal loss that mirrors that seen in the disease.
- Zongbing Hao
- , Liu Liu
- & Guanghui Wang
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Article
| Open AccessLarge-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age
Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.
- Aliza P. Wingo
- , Eric B. Dammer
- & Thomas S. Wingo
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Article
| Open AccessRestoration of high-sensitivity and adapting vision with a cone opsin
Activating the spared neurons downstream of rods and cones is a potential therapeutic approach for retinal degeneration, but has been limited by the characteristics of the opsins available. Here, the authors use medium wavelength cone opsin which has faster kinetics than others and show that it resolves some of these difficulties in a mouse model.
- Michael H. Berry
- , Amy Holt
- & Ehud Y. Isacoff
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Article
| Open AccessOrganoid-derived C-Kit+/SSEA4− human retinal progenitor cells promote a protective retinal microenvironment during transplantation in rodents
Stem cell transplantation to treat retinal degeneration could be limited by the degenerative microenvironment. Here, the authors show that C-Kit+/SSEA4– progenitor cells enriched from human embryonic stem cell derived retinal organoids protect retinal structure, suppress microglial activation, gliosis and inflammation.
- Ting Zou
- , Lixiong Gao
- & Zheng Qin Yin
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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 AccessCorrespondence between cerebral glucose metabolism and BOLD reveals relative power and cost in human brain
The brain primarily uses glucose to generate energy, but the relationship of neuronal activity to glucose utilization is not necessarily a simple linear one. Here, the authors introduce relative power (rPWR) and relative cost (rCST) as new metrics to quantify how brain activity relates to glucose consumption.
- Ehsan Shokri-Kojori
- , Dardo Tomasi
- & Nora D. Volkow
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Article
| Open AccessMicroglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits
The potential links between infections and neurodegenerative disorders are unclear. Here, Wu et al. present a mouse model of low-grade candidemia characterized by highly localized cerebritis, accumulation of amyloid precursor protein and beta peptides, and mild memory impairment that resolves with fungal clearance.
- Yifan Wu
- , Shuqi Du
- & David B. Corry
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Article
| Open AccessAcute microglia ablation induces neurodegeneration in the somatosensory system
Previous studies have shown that depletion of microglia at early developmental stages leads to neuronal death. Here the authors use an inducible system to ablate microglia in adulthood, showing that such depletion leads to ataxia-like behavior and neuronal loss, and identifying the inflammatory components that may contribute.
- Stephen J. Rubino
- , Lior Mayo
- & Howard L. Weiner
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Article
| Open AccessA therapeutic approach to pantothenate kinase associated neurodegeneration
Mutations in pantotenate kinase (PANK) cause neurodegneration. Here the authors carry out achemical screen and identify a PANK activator that is orally available, crosses the blood brain barrierand show that it effecttive in improving pathology and life span in a mouse model of the disease.
- Lalit Kumar Sharma
- , Chitra Subramanian
- & Suzanne Jackowski
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Article
| Open AccessAPOE ε2 is associated with increased tau pathology in primary tauopathy
The APOE ε4 allele is a strong genetic risk factor for Alzheimer’s disease, whereas the APOE ε2 allele is protective. Here the authors show that mice expressing the human APOE ε2/ε2 genotype have increased tau pathology and related behavioral deficits; they also find that the APOE ε2 allele is associated with an increased burden of tau pathology in postmortem human brains with progressive supranuclear palsy.
- Na Zhao
- , Chia-Chen Liu
- & Guojun Bu
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Article
| Open AccessHigh prevalence of focal and multi-focal somatic genetic variants in the human brain
Similar to cancers, somatic mutations might lead to neurodegenerative diseases. Here, the authors perform ultra-deep sequencing of 102 genes in 173 adult human brains, detect somatic mutations in 54 brains, and develop a mathematical model to estimate the frequency of mutated foci in human brains.
- Michael J. Keogh
- , Wei Wei
- & Patrick F. Chinnery
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Article
| Open AccessMiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging
miR-34 is known to regulate age-related gene expression in the Drosophila brain, and miR-34 overexpression can attenuate neurodegeneration induced by polyQ-expanded proteins. Here, Kennerdell and colleagues show that miR-34 confers longevity and neuroprotection via an epigenetic regulator Polycomb Repressive Complex 2 and molecular chaperone expression.
- Jason R. Kennerdell
- , Nan Liu
- & Nancy M. Bonini
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Article
| Open AccessCryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel
The intrinsically disordered protein alpha-synuclein (aSyn) forms polymorphic fibrils. Here the authors provide molecular insights into aSyn fibril polymorphism and present the cryo-EM structures of the two predominant species, a rod and a twister both determined at 3.7 Å resolution.
- Binsen Li
- , Peng Ge
- & Lin Jiang
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Article
| Open AccessElongator mutation in mice induces neurodegeneration and ataxia-like behavior
Elp6 is a component of the Elongator complex that regulates tRNAs and translation. Here the authors identify a mutation in the Elp6 gene that contributes to the cerebellar ataxia-like phenotype in a mutant mouse.
- Marija Kojic
- , Monika Gaik
- & Brandon J. Wainwright
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Article
| Open AccessStructural and functional analysis of mRNA export regulation by the nuclear pore complex
The export of mRNA to the cytosol depends on the nuclear pore complex (NPC) and the activation of the helicase DDX19, but their interplay in humans remains poorly understood. Here, the authors present a structural and functional analysis of DDX19 activation, revealing how the human NPC regulates mRNA export.
- Daniel H. Lin
- , Ana R. Correia
- & André Hoelz
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Article
| Open AccessArtificial strain of human prions created in vitro
Synthetic prions have previously been generated from recombinant rodent PrP. Here the authors generate synthetic human prions, by seeding human PrP with CJD prions, and characterize its infectivity in mice.
- Chae Kim
- , Xiangzhu Xiao
- & Jiri G. Safar
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Article
| Open AccessTissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease
Alexander disease is a rare neurodegeneration caused by mutations in a glial gene GFAP. Here, Wang and colleagues show in animal models of Alexander disease that GFAP mutant brain and cells have greater tissue and cellular stiffness and greater activation of mechanosensitive signaling cascade.
- Liqun Wang
- , Jing Xia
- & Mel B. Feany
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Article
| Open AccessAberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy
Mutations in glycyl-tRNA synthetase (GlyRS) cause Charcot-Marie-Tooth disease, a neuromuscular disorder characterized by axonal degeneration. Here the authors show that mutant GlyRS interacts with histone deacetylase 6, resulting in increased deacetylation of α-tubulin and axonal transport deficits.
- Zhongying Mo
- , Xiaobei Zhao
- & Xiang-Lei Yang
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Article
| Open AccessTargeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology
Progranulin (PGRN) mutations cause frontotemporal lobe dementia with TDP-43 pathology. Here the authors develop a mutant PGRN knock-in mouse model of the disease, and show that Tyro3, a tyrosine kinase membrane receptor that acts upstream of PKC and MAPK, is inhibited by PGRN which contributes to pathology in this model.
- Kyota Fujita
- , Xigui Chen
- & Hitoshi Okazawa
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Article
| Open AccessNeuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures
Neurodegeneration is increasingly associated with endolysosomal and autophagy dysfunction. Here, Miranda and colleagues show that disruption of neuronal PI3P/Vps34 signaling leads to endolysosomal membrane damage and aberrant release of undigested material in APP-CTF- and BMP-positive exosomes.
- André M. Miranda
- , Zofia M. Lasiecka
- & Gilbert Di Paolo
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Article
| Open AccessSynaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson’s disease-like pathology
Mutations in the parkin, an ubiquitin ligase, are linked to Parkinson’s disease. Here the authors show that synaptotagmin-11 is a parkin substrate and that its upregulation affects dopamine release, triggers degeneration, and causes motor impairment.
- Changhe Wang
- , Xinjiang Kang
- & Zhuan Zhou
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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 AccessCis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae
Induction of the cis form of phosphorylated tau (cis P-tau) has previously been shown to occur in animal models of traumatic brain injury (TBI), and blocking this form of tau using antibody was beneficial in a rodent model of severe TBI. Here the authors show that cis P-tau induction is a feature of several different forms of TBI in humans, and that administration of cis P-tau targeting antibody to rodents reduces or delays pathological features of TBI.
- Onder Albayram
- , Asami Kondo
- & Xiao Zhen Zhou
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Article
| 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 AccessDivergent prion strain evolution driven by PrPC expression level in transgenic mice
PrPC protein plays a key role in prion transmission across species. Here, the authors compare transmission of a representative scrapie isolate to transgenic mice expressing variable levels of the same Prnp allele as the donor sheep, and find divergent strain propagation regulated by PrPCgene dosage.
- Annick Le Dur
- , Thanh Lan Laï
- & Hubert Laude