Featured
-
-
Article |
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
-
Article
| 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
-
Article |
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
-
Article |
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
-
Article |
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
-
Article
| 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
-
Article
| 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
-
Article |
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
-
Article |
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
-
Article |
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
-
Article |
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
-
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
-
Article
| 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
-
Article |
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
-
Article
| 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
-
Article |
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
-
Article |
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
-
Article |
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
-
Article |
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
-
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
-
Article |
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
-
Article |
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
-
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
-
Article
| 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
-
Article |
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
-
Article |
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
-
Article |
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
-
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
-
Article |
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
-
Article |
Sulfhydration mediates neuroprotective actions of parkin
The gasotransmitter hydrogen sulfide signals by sulfide modification of target proteins. Vandiver and colleagues study the sulfhydration of parkin by hydrogen sulfide and find that sulfhydration stimulates its activity, and that this activity is reduced in patients with Parkinson’s disease.
- M. Scott Vandiver
- , Bindu D. Paul
- & Solomon H. Snyder
-
Article |
Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours
Synaptic plasticity in the nucleus accumbens is implicated in stress and addiction. Sim et al. study mice deficient in dopamine D2 receptors, and find an increase in anxiety behaviour and reduced addictive behaviour in response to stress, both of which are associated with changes in nucleus accumbens activity.
- Hye-ri Sim
- , Tae-Yong Choi
- & Ja-Hyun Baik
-
Article |
Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia
Parkinson’s disease is associated with the accumulation of abnormal aggregates of α-synuclein and microglial neuroinflammation. Kim et al. show that α-synuclein oliogomers released by neurons activate microglia by stimulating Toll-like receptor 2 signalling in these cells.
- Changyoun Kim
- , Dong-Hwan Ho
- & Seung-Jae Lee
-
Article |
Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex
Expansion of CAG repeats in messenger RNAs is a common feature of various neurodegenerative disorders, including Huntington’s disease. Krauß et al.show that messenger RNAs with expanded CAG repeats bind to a protein complex that regulates translation and promotes overproduction of such aberrant proteins.
- Sybille Krauß
- , Nadine Griesche
- & Susann Schweiger
-
Article |
Holographic optogenetic stimulation of patterned neuronal activity for vision restoration
Photo-stimulation can be used to control neuronal circuits, but current strategies lack optimal precision and resolution. Reutsky-Gefen et al. demonstrate a potential approach for vision restoration via holographically patterned, optogenetic stimulation of retinal ganglion cells, with temporal precision.
- Inna Reutsky-Gefen
- , Lior Golan
- & Shy Shoham
-
Article |
Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease
A link between smoking and the incidence of Alzheimer’s disease has been implicated in humans. In this study, transgenic mouse models of Alzheimer’s disease exposed to cigarette smoke display increased disease abnormalities in the brain, such as amyloidogenesis, neuroinflammation and tau phosphorylation.
- Ines Moreno-Gonzalez
- , Lisbell D. Estrada
- & Claudio Soto
-
Article |
Cytotoxicity of botulinum neurotoxins reveals a direct role of syntaxin 1 and SNAP-25 in neuron survival
Botulinum toxins can cause substantial neurodegeneration. Peng et al. study cultured rat hippocampal neurons and find that botulinum toxin-induced cytotoxicity occurs only when there is effective cleavage of the SNARE proteins, syntaxin 1 or SNAP-25, by type C and type E botulinum toxins.
- Lisheng Peng
- , Huisheng Liu
- & Min Dong
-
Article |
Perceiving invisible light through a somatosensory cortical prosthesis
Primary sensory areas of newborn mammals typically display input-dependent plasticity. Thomson and colleagues use a sensory prosthetic device in rats to show that adult rats can discriminate different infrared light signals, when the signals are routed to somatosensory cortex by electrical microstimulation.
- Eric E. Thomson
- , Rafael Carra
- & Miguel A.L. Nicolelis
-
Article
| Open AccessA point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration
Semaphorin 4A is implicated in photoreceptor survival. Nojima and colleagues generate transgenic mice with different mutations in the Sema4A gene and find that point mutation of F350 causes severe degeneration in photoreceptor cells, which can be rescued by virus-mediated gene therapy.
- Satoshi Nojima
- , Toshihiko Toyofuku
- & Atsushi Kumanogoh
-
Article
| Open AccessOn-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy
Temporal lobe epilepsy in adults does not always respond to treatment. Krook-Magnuson and colleagues use optogenetics to inhibit and activate excitatory and inhibitory neurons, respectively, in a mouse model of temporal lobe epilepsy, and find that they can stop seizures on a moment-to-moment basis.
- Esther Krook-Magnuson
- , Caren Armstrong
- & Ivan Soltesz
-
Article |
A safe lithium mimetic for bipolar disorder
Lithium is commonly used to treat bipolar disorder, but it exerts side effects at doses close to the therapeutic range. Singh and colleagues screen a collection of clinical compounds and find that ebselen induces lithium-like effects on mouse models of bipolar disorder by inhibiting inositol monophosphatase.
- Nisha Singh
- , Amy C. Halliday
- & Grant C. Churchill
-
Article |
Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila
PAR-1 inDrosophilahas been identified as a key physiological tau kinase. Lee and colleagues perform genetic screens for regulators of PAR-1 and find that it is targeted for ubiquitination and degradation by the ubiquitin ligase complex SCF(Slimb), and that this pathway modulates synaptic morphology.
- Seongsoo Lee
- , Ji-Wu Wang
- & Bingwei Lu
-
Article
| Open AccessRapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex
Tuberous sclerosis complex is an autosomal dominant cognitive disorder caused by mutations affecting TSCgenes. Sato and colleagues examine tuberous sclerosis complex mutant mice and find that the behavioural and anatomical abnormalities can be reversed by inhibiting rapamycin-sensitive signalling pathways, even in adulthood.
- Atsushi Sato
- , Shinya Kasai
- & Masashi Mizuguchi
-
Article |
A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology
The mislocalization and downregulation of the proteins TDP-43 and ADAR2, respectively, are implicated in amyotrophic lateral sclerosis pathology. Yamashita et al. find that downregulation of ADAR2 results in calcium-permeable AMPA receptor-mediated calpain activation and subsequent aberrant cleavage of TDP-43.
- Takenari Yamashita
- , Takuto Hideyama
- & Shin Kwak
-
Article |
Structural modelling and mutant cycle analysis predict pharmacoresponsiveness of a Nav1.7 mutant channel
Mutations of the NaV1.7 voltage-gated sodium channel are implicated in abnormal pain signal transduction. Yang and colleagues perform structural modeling, mutant cycle analysis and electrophysiology on specific mutants and find that they can accurately predict their response profiles to channel blockers.
- Yang Yang
- , Sulayman D. Dib-Hajj
- & Stephen G. Waxman
-
Article
| Open AccessStructural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons
Mutations in human angiogenin are implicated in the progression of amyotrophic lateral sclerosis. Thiyagarajan and colleagues show that structural differences between angiogenin variants affect neuronal survival, and the ability to induce stress granules in neuronal cell lines.
- Nethaji Thiyagarajan
- , Ross Ferguson
- & K. Ravi Acharya
-
Article
| Open AccessEvidence of an inhibitory restraint of seizure activity in humans
Seizure activity in the brain is characterized by the recruitment of cortical neuronal activity. Schevon and colleagues study seizure activity in human subjects and find that the recruitment of neurons is hypersynchronous and that there is an intrinsic restraint on the propagation of this activity.
- Catherine A. Schevon
- , Shennan A. Weiss
- & Andrew J. Trevelyan
-
Article |
Structured neuronal encoding and decoding of human speech features
Speech is encoded by the firing patterns of speech-controlling neurons in different regions of the brain, which Tankus and colleagues analyse in this study. They find highly specific encoding of vowels in medial–frontal neurons and nonspecific tuning in superior temporal gyrus neurons.
- Ariel Tankus
- , Itzhak Fried
- & Shy Shoham
-
Article
| Open AccessTargeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury
Claudin-5 is a component of tight junctions and has important roles in mediating the permeability of the blood-brain barrier. Campbell and co-workers administer short interfering RNA against claudin-5 in a model of brain injury, finding that it enhances water movement from the brain to the blood and alleviates swelling.
- Matthew Campbell
- , Finnian Hanrahan
- & Peter Humphries
-
Article |
Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation
The loss of neurotrophic factors is responsible for key neurodegenerative processes in Alzheimer's disease. In this study, Obregon and colleagues treat amyloidogenic cells with the neurotrophin soluble amyloid precursor protein-α and find that it halts amyloidogenesis by interacting with the β-secretase BACE1.
- Demian Obregon
- , Huayan Hou
- & Jun Tan
Browse broader subjects
Browse narrower subjects
- Addiction
- Alzheimer's disease
- Amyotrophic lateral sclerosis
- Anxiety
- Autism spectrum disorders
- Bipolar disorder
- Cancer in the nervous system
- Channelopathies
- Chronic pain
- Dementia
- Depression
- Developmental disorders
- Dystonia
- Encephalopathy
- Epilepsy
- Huntington's disease
- Lipid-storage diseases
- Macular degeneration
- Multiple sclerosis
- Neurodegeneration
- Obsessive compulsive disorder
- Parkinson's disease
- Post-traumatic stress disorder
- Psychosis
- Schizophrenia
- Spinocerebellar ataxia
- Stress and resilience
- Stroke