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Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia
Parkinson’s disease and L-DOPA-induced dyskinesia are both associated with imbalances in activity between populations of spiny projection neurons. Fieblinger et al.show that homeostatic adaptations in excitability are engaged by these disease states, but synaptic strengths are not scaled accordingly.
- Tim Fieblinger
- , Steven M. Graves
- & D. James Surmeier
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De novo TBR1 mutations in sporadic autism disrupt protein functions
Autism spectrum disorders (ASD) are characterized by social impairments, communication deficits and repetitive stereotyped behaviours. Here, the authors show that de novo missense mutations, but not inherited missense mutations, in TBR1disrupt the protein function and contribute to ASD aetiology.
- Pelagia Deriziotis
- , Brian J. O’Roak
- & Simon E. Fisher
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Metabolic properties in stroked rats revealed by relaxation-enhanced magnetic resonance spectroscopy at ultrahigh fields
1H magnetic resonance can detect endogenous metabolites at physiological concentrations but its application in animal models is challenged by low sensitivity. Here the authors focus ultrahigh magnetic fields on metabolites whose spectral signatures are selectively excited, and achieve microarchitectural insight of rat brains after a stroke.
- Noam Shemesh
- , Jens T. Rosenberg
- & Lucio Frydman
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Lifespan maturation and degeneration of human brain white matter
White matter in the human brain is known to change its properties during an individual's lifespan. Here, Yeatman et al. use quantitative imaging measurements of the living human brain to model changes in white mater structure based on tissue development and decline between the ages of 7–85 years.
- Jason D. Yeatman
- , Brian A. Wandell
- & Aviv A. Mezer
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Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein
Transmission of alpha-synuclein aggregates between neurons has been observed in animal models of Parkinson’s disease, however, the mechanism of transmission remains unclear. Bae et al. report that a cycle of uptake, co-aggregation and exocytosis is enhanced by loss of glucocerebrosidase activity.
- Eun-Jin Bae
- , Na-Young Yang
- & Seung-Jae Lee
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Enhanced synapse remodelling as a common phenotype in mouse models of autism
Impaired neuronal connectivity is implicated in autism spectrum disorder (ASD). In this study, the authors perform time-lapse imaging of brain neurons from different mouse models of ASD and provide evidence for enhanced turnover of excitatory synapses as a commonly occurring mechanism in ASD.
- Masaaki Isshiki
- , Shinji Tanaka
- & Shigeo Okabe
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Neuroplasticity-based computerized cognitive remediation for treatment-resistant geriatric depression
As well as substantial changes in mood, geriatric depression is also characterized by executive dysfunction (ED). Morimoto et al.show that some sufferers of geriatric depression do not respond to conventional drugs, and that ED in these patients can be alleviated with computerized cognitive remediation therapy.
- Sarah Shizuko Morimoto
- , Bruce E. Wexler
- & George S. Alexopoulos
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| Open AccessSelective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model
Tuberous sclerosis complex (TSC) is a rare genetic condition characterized by epileptic seizures that start in infancy. Here, the authors show that these seizures are modulated by GluN2C-containing NMDA receptors in the cortex of a mouse model of TSC, and that suppressing their activity attenuates seizures.
- N. Lozovaya
- , S. Gataullina
- & N. Burnashev
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| Open AccessModest CaV1.342-selective inhibition by compound 8 is β-subunit dependent
Compound 8-1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6(1H,3H,5H)-trione was previously reported to be a selective inhibitor of the CaV1.3 calcium channel. Now, Huang et al. demonstrate that selectivity towards CaV1.3 relative to CaV1.2 is dependent on the type of β-subunit and CaV1.3 splice variant assayed.
- Hua Huang
- , Cheng Yang Ng
- & Tuck Wah Soong
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| Open AccessDisrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome
Cerebro–costo–mandibular syndrome, CCMS, is a severe human multiple malformation disorder. Here, the authors report that mutations in SNRPBdisrupt the normal regulation of alternative splicing at this gene, and in so doing, may be responsible for the development of CCMS.
- Danielle C. Lynch
- , Timothée Revil
- & Francois P. Bernier
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An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry
Abnormal accumulation of the RNA-binding protein FUS and mutations within the FUS gene have been found in association with amyotrophic lateral sclerosis (ALS). Here, Dini Modigliani et al.uncover a FUS regulatory circuit that implicates the microRNAs miR-141 and miR-200a in a feedback loop disrupted by an ALS-associated mutation.
- Stefano Dini Modigliani
- , Mariangela Morlando
- & Irene Bozzoni
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Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour
α-synuclein is a protein whose aberrant aggregation is associated with Parkinson’s disease. Here, Fusco et al.characterize α-synuclein bound to lipid membranes using a combination of solution and solid-state NMR spectroscopy and provide insights into the molecular processes associated with the aggregation of this protein.
- Giuliana Fusco
- , Alfonso De Simone
- & Gianluigi Veglia
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| Open AccessChemical–genetic attenuation of focal neocortical seizures
Focal epilepsy is difficult to treat with currently available drugs or surgical approaches. Kätzel et al.express mutant inhibitory receptors in the brains of rats with focal epilepsy and selectively activate these receptors by an exogenous compound, which results in region- and time-specific suppression of focal seizures
- Dennis Kätzel
- , Elizabeth Nicholson
- & Dimitri M. Kullmann
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CRL4ACRBN E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis
Ion channel mutations are implicated in epilepsy but post-translational modification of these channels is poorly understood. Here, Liu et al.show that mice with mutations in a specific E3 ubiquitin ligase that post-translationally modifies voltage-activated potassium channels may also contribute to epilepsy symptoms.
- Jiye Liu
- , Jia Ye
- & Yong Cang
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The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages
The ketone body β-hydroxybutyrate is produced in the liver in response to a ketogenic diet. Here, Rahman et al. show that β-hydroxybutyrate mediates the neuroprotective effect of a ketogenic diet by activating the HCA2receptor on a neuroprotective subset of macrophages.
- Mahbubur Rahman
- , Sajjad Muhammad
- & Markus Schwaninger
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Modulation of dopamine release in the striatum by physiologically relevant levels of nicotine
Nicotine exposure from cigarette smoke modulates dopamine release in the brain, which is implicated in nicotine addiction, but how it does this is unclear. Here, in mouse brain slices, the authors show that nicotine inhibits cholinergic- but not dopaminergic-dependent dopamine release.
- Li Wang
- , Shujiang Shang
- & Zhuan Zhou
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| Open AccessRhythmic oscillations of the microRNA miR-96-5p play a neuroprotective role by indirectly regulating glutathione levels
Glutathione is a key antioxidant that plays an important neuroprotective role in the brain. Here, Kinoshita et al.show that levels of glutathione exhibit diurnal fluctuations that are indirectly regulated by the microRNA miR-96-5p, and that this microRNA plays a neuroprotective role against oxidative stress.
- Chisato Kinoshita
- , Koji Aoyama
- & Toshio Nakaki
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Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52
Impaired clearance of aberrantly phosphorylated tau protein is implicated in Alzheimer’s Disease. Jo et al.show that nuclear factor Nrf2 participates in the clearance of phosphorylated tau protein in the brain by inducing the autophagy adaptor protein NDP52.
- Chulman Jo
- , Soner Gundemir
- & Gail V. W. Johnson
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Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease
Reelin is crucial for brain development and controls neurogenesis and synaptic plasticity in the adult brain. Here, Pujadas et al. reveal that Reelin slows the onset of Alzheimer’s disease in a mouse model by delaying the formation of amyloid fibrils and preventing neuronal loss and cognitive decline.
- Lluís Pujadas
- , Daniela Rossi
- & Eduardo Soriano
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| Open AccessmGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo
In Alzheimer's disease, the soluble amyloid beta peptide is known to modulate synaptic function by forming a complex with prion proteins and metabotropic glutamate receptors. Here, Hu et al.show that amyloid beta signalling via this complex facilitates the induction of long-term depression at synapses.
- Neng-Wei Hu
- , Andrew J. Nicoll
- & Michael J. Rowan
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Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease
Beta amyloid aggregation, a process implicated in Alzheimer’s disease pathology, is inhibted by polyoxometalate with a Wells–Dawson structure. Gao et al.show that transition metal-functionalized derivatives are more effective at inhibiting beta amyloid aggregation than non-functionalized derivatives.
- Nan Gao
- , Hanjun Sun
- & Xiaogang Qu
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| Open AccessDifferential methylation of the TRPA1 promoter in pain sensitivity
Genetically identical twins provide a valuable resource to identify epigenetic factors associated with complex traits. Here the authors adopt this approach and find that differential methylation of the pain gene TRPA1is associated with pain sensitivity in humans.
- J.T. Bell
- , A.K. Loomis
- & T.D. Spector
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Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain
Peptide drugs are attractive as therapeutics for gut-based applications, although they may be susceptible to reduction and degradation. Here, the authors develop seleno-oxytocin analogues, with enhanced stability at no cost to potency, and demonstrate their efficacy at colonic nociceptor inhibition in a mouse model.
- Aline Dantas de Araujo
- , Mehdi Mobli
- & Paul F. Alewood
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Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site
In Alzheimer’s disease, familial mutations of the amyloid precursor protein (APP) can increase the production of the toxic cleavage product Aß42. Here, Chen et al. show that mutations within the transmembrane domain of APP favour Aß42 production by increasing the accessibility of the ε-cleavage site.
- Wen Chen
- , Eric Gamache
- & Chunyu Wang
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Postnatal muscle modification by myogenic factors modulates neuropathology and survival in an ALS mouse model
MyoD and myogenin are muscle regulatory factors that are involved in muscle development. Park et al.study a mouse model of amyotrophic lateral sclerosis and find that MyoD and myogenin have positive and negative effects, respectively, on motor neuron degeneration and muscle denervation.
- Kevin H. J. Park
- , Sonia Franciosi
- & Blair R. Leavitt
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| Open AccessRETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Pericytes are cells in the blood–brain barrier that degenerate with the onset of Alzheimer's disease. Here, Sagare et al. show that pericyte loss contributes to disease onset by promoting amyloid-beta accumulation, tau pathology and early loss of neuronal cells.
- Abhay P. Sagare
- , Robert D. Bell
- & Berislav V. Zlokovic
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| Open AccessA failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice
Defective ascorbic acid flux is a sign of metabolic failure associated with Huntington’s disease. Here, Acuña et al.show that reduction in ascorbic acid flux from astrocytes precedes the symptoms of Huntington’s disease in mice and impairs ascorbic acid uptake in neurons.
- Aníbal I. Acuña
- , Magdalena Esparza
- & Maite A. Castro
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Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition
Mutations in the GABA A receptor have been implicated in alcohol dependence in humans. In this study, the authors show that mice with mutations in the beta 1 subunit of the GABA A receptor exhibit spontaneous GABA A channel opening and preferentially consume alcohol, working harder to access it.
- Quentin M. Anstee
- , Susanne Knapp
- & Howard C. Thomas
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Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress
Large insoluble aggregates of huntingtin are believed to contribute to the onset of Huntington’s disease, partly by interfering with endoplasmic reticulum-associated protein degradation. Leitman et al.show that huntingtin interferes with protein degradation before it forms insoluble aggregates.
- Julia Leitman
- , F. Ulrich Hartl
- & Gerardo Z. Lederkremer
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Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression
Long-term depression of synapses is mediated by the endocytosis of AMPA receptors. Matsuda et al.show that stargazin mediates both AMPA receptor internalization and subsequent endosomal sorting through sequential interactions with two different endocytic adapters.
- Shinji Matsuda
- , Wataru Kakegawa
- & Michisuke Yuzaki
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Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression
Methylphenidate, the active compound in Ritalin, is used to treat attention and hyperactivity disorders, but it is also taken for recreational use. Calipari et al.show that high-dose methylphenidate leads to enhanced dopaminergic responses to amphetamines, and enhanced amphetamine-seeking behaviour in rats.
- Erin S. Calipari
- , Mark J. Ferris
- & Sara R. Jones
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Article
| Open AccessStructural and functional characterization of two alpha-synuclein strains
α-synuclein is implicated in neurodegenerative diseases. Bousset et al. generate two α-synuclein polymorphs and find differences in aggregation, function and toxicity, suggesting that these altered properties may be the cause for differences in disease progression.
- Luc Bousset
- , Laura Pieri
- & Ronald Melki
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| Open AccessSubstrate ectodomain is critical for substrate preference and inhibition of γ-secretase
γ-Secretase inhibitors are studied for their potential to treat Alzheimer’s disease, but their use is limited by side effects. Funamoto et al.show that γ-secretase preferentially cleaves substrates with short ectodomains and that inhibitors based on these ectodomains reduce disease-like pathology in mice.
- Satoru Funamoto
- , Toru Sasaki
- & Yasuo Ihara
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Miz1 is required to maintain autophagic flux
Miz1 is a binding partner of the transcription factor c-Myc and a regulator of cell cycle progression. Wolf et al. show that inactivation of Miz1 in the mouse central nervous system results in neurodegeneration, and find that Miz1 is essential for the transcriptional regulation of autophagic flux.
- Elmar Wolf
- , Anneli Gebhardt
- & Martin Eilers
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| Open AccessAmyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity
Prion protein has been suggested to bind toxic amyloid-ß oligomers. Nicollet al.demonstrate that binding to prion protein and prion protein-dependent synaptotoxicity correlate with the presence of a tubular form of amyloid-ß with a defined triple helical structure.
- Andrew J. Nicoll
- , Silvia Panico
- & John Collinge
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Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment
Scn1a encodes a voltage-gated sodium channel and mutations in this gene are implicated in epilepsy. Baraban et al. find that the compound clemizole is effective in blocking epilepsy-like seizures zebrafish with an Scn1adevelopmental mutation.
- Scott C. Baraban
- , Matthew T. Dinday
- & Gabriela A. Hortopan
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Placental programming of anxiety in adulthood revealed by Igf2-null models
Insulin-like growth factor-2 is implicated in foetal and placental development in mammals. Mikaelsson et al. study transgenic mice with disrupted insulin-like growth factor-2 signalling and find that their offspring are more anxious when they reach adulthood.
- Mikael Allan Mikaelsson
- , Miguel Constância
- & Trevor Humby
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Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
Clinical trials of γ-secretase inhibitors to treat Alzheimer’s disease show that side effects occur from their non-selective action. Dimitrov et al.show that improved second generation γ-secretase modulators spare cleavage sites of substrate proteins that are implicated in the side effects.
- Mitko Dimitrov
- , Jean-René Alattia
- & Patrick C. Fraering
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Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system
Endosomal sorting is regulated by phosphatidylinositol-3-phosphate and anomalies in this process are implicated in Alzheimer’s disease. Here the authors show that deficiency of phosphatidylinositol-3-phosphate in vitroenhances the pathological trafficking and processing of amyloid precursor protein.
- Etienne Morel
- , Zeina Chamoun
- & Gilbert Di Paolo
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Article
| Open AccesshESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury
Astroglia are heterogeneous in phenotype and not all astrocytes are equivalent in their ability to repair injured brain. Here, the authors show that two defined subtypes of astroglia generated from hESC-derived Olig2-positive versus Olig2-negative neural progenitors, exhibit distinct properties and neuroprotective effects.
- Peng Jiang
- , Chen Chen
- & Wenbin Deng
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Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma
Impairments in cerebral folate transport are implicated in childhood-onset neurodegeneration. Grapp et al. show that folate receptors in the choroid plexus mediate folate transport by delivering folate receptor-containing exosomes into the brain parenchyma.
- Marcel Grapp
- , Arne Wrede
- & Robert Steinfeld
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Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression
The scavenger receptor Scara1, expressed on microglia and macrophages, binds beta amyloid aggregates. In a mouse model of Alzheimer’s disease, the authors show that Scara1deficiency is associated with reduced clearance and increased deposition of aggregates in the brain, which results in early mortality.
- Dan Frenkel
- , Kim Wilkinson
- & Joseph El Khoury
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Article
| Open AccessA molecular explanation for the recessive nature of parkin-linked Parkinson’s disease
Mutations in the E3 ubiquitin ligase parkin are associated with juvenile Parkinson’s disease. Here the authors report the solution structure of the Parkin RING2 domain, revealing how disease-associated mutations affect its function and providing a molecular explanation for the recessive nature of the disease.
- Donald E. Spratt
- , R Julio Martinez-Torres
- & Gary S. Shaw
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| Open AccessStructure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases
The Parkinson’s disease-associated protein Parkin regulates the fate of damaged mitochondria by ubiquitinating mitochondrial substrates. Riley et al. present the crystal structure of the Parkin-R0RBR domain, providing new insight into the catalytic mechanism of the enzyme.
- B.E. Riley
- , J.C. Lougheed
- & J.A. Johnston
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Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice
Aberrant caspase signalling is implicated in Alzheimer’s disease. Pozueta et al.study a mouse model of Alzheimer’s disease that is deficient in caspase-2 and find that surprisingly, these mice don’t display impaired cognitive function, or the reduced dendritic spine density normally associated with the disease.
- Julio Pozueta
- , Roger Lefort
- & Michael Shelanski
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SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs
Ataxia telangiectasia is a genetic disease that results in various pathological disorders. In this study, the authors develop an in vitromodel of Ataxia telangiectasia using human induced pluripotent stem cells, and find that physiological defects can be alleviated by small molecule read-through compounds.
- Peiyee Lee
- , Nathan T. Martin
- & William E. Lowry
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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases
Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.
- Kyota Fujita
- , Yoko Nakamura
- & Hitoshi Okazawa
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Article
| Open AccessLigand binding and aggregation of pathogenic SOD1
Mutations of the SOD1gene are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis. Wright and colleagues find that SOD1 aggregation in cells is arrested by compounds that bind at the core of SOD1 aggregates, rather than at the dimer interface site.
- Gareth S.A. Wright
- , Svetlana V. Antonyuk
- & S Samar Hasnain
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Dynamic switching of calmodulin interactions underlies Ca2+ regulation of CaV1.3 channels
Calmodulin regulation of Ca2+ channels is an important Ca2+-feedback system. The structural underpinnings of this modulation are unclear, but this study reports the molecular states underlying channel regulation.
- Manu Ben Johny
- , Philemon S. Yang
- & David T. Yue
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