Featured
-
-
Article
| Open AccessClosed-loop direct control of seizure focus in a rodent model of temporal lobe epilepsy via localized electric fields applied sequentially
Direct stimulation of the focus of a seizure may have potential for the treatment of epilepsy. Here the authors demonstrate in a rat model a sequential narrow-field stimulation method for terminating seizures.
- Wonok Kang
- , Chanyang Ju
- & Sung-Min Park
-
Article
| Open AccessExperimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae
The poor correlation between brain Aβ deposition and clinical symptoms in Alzheimer´s disease remains puzzling. Here, the authors show a temporal dissociation of Aβ deposition and neurodegeneration.
- Christine Rother
- , Ruth E. Uhlmann
- & Mathias Jucker
-
Article
| Open AccessEnhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model
Mutations that enhance the activity of protein kinase C alpha (PKCα) are associated with Alzheimer’s Disease. Here, the authors report that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model.
- Gema Lordén
- , Jacob M. Wozniak
- & Alexandra C. Newton
-
Article
| Open AccessPrematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS
Nuclear depletion and cytoplasmic accumulation of splicing factor SFPQ are hallmarks of ALS. Here the authors demonstrate a relationship between loss of SFPQ and the emergence in neurites of intron-retaining mRNAs enriched in ALS models and tissues.
- Richard Taylor
- , Fursham Hamid
- & Corinne Houart
-
Article
| Open AccessActivated astrocytes attenuate neocortical seizures in rodent models through driving Na+-K+-ATPase
Neocortical epilepsy is resistant to current treatments. Zhao et al. report that optogenetic stimulation of astrocytes effectively attenuates seizures via driving Na+-K+-ATPase, indicating a potential treatment strategy for intractable epilepsy.
- Junli Zhao
- , Jinyi Sun
- & Yi Wang
-
Article
| Open AccessNorepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Sympathetic neurons are affected in familial dysautonomia, a rare disease associated with a mutation in ELP1, but the mechanisms are not fully understood. Here the authors show, using neurons derived from participants with familial dysauotnomia, that spontaneous sympathetic neuron hyperactivity is observed and is associated with norepinephrine transporter deficits.
- Hsueh-Fu Wu
- , Wenxin Yu
- & Nadja Zeltner
-
Article
| Open AccessCBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder
Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects.
- Aurélie de Thonel
- , Johanna K. Ahlskog
- & Valérie Mezger
-
Article
| Open AccessDOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers
In this work, the authors show that α-synuclein is posttranslationally dopanized at Tyr136 by tyrosine hydroxylase, which facilitates the formation of oligomers. This modification likely impacts pathogenesis and the selective degeneration of dopaminergic neurons in Parkinson’s disease.
- Mingyue Jin
- , Sakiko Matsumoto
- & Shinji Hirotsune
-
Article
| Open AccessHypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia
Developing brain-protective hypothermia is a medical challenge. Here, the authors show that deep brain stimulation of a particular brain area is a new way to trigger the body into a hibernation-like state with reduced body temperature and brain protection in a mouse model of stroke.
- Shuai Zhang
- , Xinpei Zhang
- & Sheng-Tao Hou
-
Article
| Open AccessDevelopmental disruption and restoration of brain synaptome architecture in the murine Pax6 neurodevelopmental disease model
Brain-wide mapping of synapse molecular composition in Pax6 mutant mice shows remodelling and restoration of synaptome architecture during development, a possible means of conferring resilience to genetic disorders.
- Laura Tomas-Roca
- , Zhen Qiu
- & Seth G. N. Grant
-
Article
| Open AccessAmyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease
The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.
- Alexa Pichet Binette
- , Nicolai Franzmeier
- & Oskar Hansson
-
Article
| Open AccessCholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer’s disease
Sleep-disordered breathing is a risk factor for Alzheimer’s disease. Here the authors use mesopontine tegmentum lesion to model sleep disordered breathing in a mouse model of Alzheimer’s disease, and find that some features of the Alzheimer’s disease-like phenotype are exacerbated.
- Lei Qian
- , Oliver Rawashdeh
- & Elizabeth J. Coulson
-
Article
| Open AccessRescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
The molecular mechanisms underlying deficits in Down syndrome remain unclear. Here, the authors show that copy number restoration of a chromatin remodeler in trisomic mice is sufficient to rescue epigenomic, physiological and cognitive deficits.
- Sasha L. Fulton
- , Wendy Wenderski
- & Ian Maze
-
Article
| Open AccessCRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro
A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of ALS and FTD. Here, the authors demonstrate CRISPR/Cas9 excision of the expansion results in a rescue of disease mechanisms in vivo and in vitro.
- Katharina E. Meijboom
- , Abbas Abdallah
- & Christian Mueller
-
Article
| Open AccessSingle cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model
Single cell RNA-sequencing of the AstTau neuron-asteroid tau assembloid model reveals excitatory neuron inflammatory signatures and an astrocytic heat shock response similar to that occurring in the brains of individuals with tauopathies, which can be ameliorated with a neuroprotective HSP90 inhibitor.
- Hannah Drew Rickner
- , Lulu Jiang
- & Christine S. Cheng
-
Article
| Open AccessPrevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders
DNA damage has been implicated in aging and neurodegeneration. Here, the authors develop a bioinformatic method to detect deletions in single neuron genome sequences and reveal an increased burden of somatic deletions during aging and in DNA repair disorders.
- Junho Kim
- , August Yue Huang
- & Eunjung Alice Lee
-
Article
| Open AccessPericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure
Using in vivo two-photon imaging, Berthiaume et al. demonstrate how pericyte loss during aging could contribute to deterioration of cerebral blood flow. They also show how pericyte remodeling reduces the deleterious effects of pericyte loss.
- Andrée-Anne Berthiaume
- , Franca Schmid
- & Andy Y. Shih
-
Article
| Open AccessDeficiency of the frontotemporal dementia gene GRN results in gangliosidosis
Progranulin-deficieny results in gangliosidosis due to reduced lysosomal lipids (BMP) required for ganglioside degradation. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD.
- Sebastian Boland
- , Sharan Swarup
- & Robert V. Farese Jr
-
Article
| Open AccessModeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes
Our understanding of human brain development in health and disease is limited. The authors generated human brain organoids from stem cell-derived isolated single neural rosettes to study human cortico-striatal development and deficits caused by an autism-associated genetic abnormality in SHANK3.
- Yueqi Wang
- , Simone Chiola
- & Aleksandr Shcheglovitov
-
Article
| Open AccessChemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington’s disease models
Chemically modified siRNAs distinguish between mutant and normal huntingtin based on a single nucleotide difference and lower mutant huntingtin specifically in patient derived cells and in a mouse model of Huntington’s disease.
- Faith Conroy
- , Rachael Miller
- & Edith L. Pfister
-
Article
| Open AccessRegional gene expression signatures are associated with sex-specific functional connectivity changes in depression
The neural substrates of depression may differ by sex. Here the authors show that depression is associated with distinct brain connectivity changes in men and in women that are explained by sex-specific transcriptomic signatures involving genes previously implicated in synapse function, immune signalling, and depression risk.
- Aleksandr Talishinsky
- , Jonathan Downar
- & Conor Liston
-
Article
| Open AccessIntracellular energy controls dynamics of stress-induced ribonucleoprotein granules
Stress granules are associated with neurodegenerative diseases. Here, Wang et al. found intracellular energy deficiencies trigger a unique type of granules and disrupt granule disassembly through 4EBP1/eIF4A.
- Tao Wang
- , Xibin Tian
- & Jiou Wang
-
Article
| Open AccessPreclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration
The authors show in an animal model and in a study in patients with dementia with Lewy bodies (DLB) that the drug neflamapimod has potential to treat diseases, such as DLB, associated with loss of neurons that produce the neurotransmitter acetylcholine.
- Ying Jiang
- , John J. Alam
- & Ralph A. Nixon
-
Article
| Open AccessSmall soluble α-synuclein aggregates are the toxic species in Parkinson’s disease
α-synuclein aggregates cause neuronal damage, but their heterogeneity complicates studying their toxic properties. Here, the authors analyze α-synuclein aggregates in vitro and study post-mortem brain samples, providing evidence that small aggregates are the main culprit for neuronal death in Parkinson’s disease.
- Derya Emin
- , Yu P. Zhang
- & David Klenerman
-
Article
| Open AccessStructure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro
Evidence suggests that fibrous aggregates of protein tau may be the proximal cause of Alzheimer’s disease. Here, using atomic structures of tau fibrils from brains of people with Alzheimer’s disease, the authors have found small-molecule drug leads that disaggregate tau fibrils in vitro.
- Paul M. Seidler
- , Kevin A. Murray
- & David S. Eisenberg
-
Article
| Open AccessRetromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau
Tau and the Retromer complex are both linked to Parkinson’s and Alzheimer’s disease. Using Drosophila neurodegeneration models, this study finds that low retromer activity induces a specific increase of a highly toxic truncated form of human Tau.
- Jamshid Asadzadeh
- , Evelyne Ruchti
- & Brian D. McCabe
-
Article
| Open AccessEarly postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming
ARID1B is a chromatin remodeler associated with autism spectrum disorders. Here the authors demonstrate that early postnatal serotonin modulation prevents adult stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming.
- Hyosang Kim
- , Doyoun Kim
- & Eunjoon Kim
-
Article
| Open AccessDesigned peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly
Amyloid self-assembly is linked to type 2 diabetes and Alzheimer’s disease. Here the authors designed constrained peptides which are nanomolar amyloid inhibitors of the key polypeptides IAPP and Aβ42 and act via supramolecular nanofiber co-assembly.
- Karin Taş
- , Beatrice Dalla Volta
- & Aphrodite Kapurniotu
-
Article
| Open AccessCholinergic basal forebrain nucleus of Meynert regulates chronic pain-like behavior via modulation of the prelimbic cortex
The basal nucleus of Meynert (NBM) plays a role in cognition by modulating cortical circuits. Here, the authors demonstrate plasticity of the NBM upon tissue injury, and that activating NBM cholinergic-GABAergic projections to the prefrontal cortex alleviates chronic pain-like behaviour in mice.
- Manfred J. Oswald
- , Yechao Han
- & Rohini Kuner
-
Article
| Open AccessDiscrete subicular circuits control generalization of hippocampal seizures
The subiculum is known to contribute to seizures in epilepsy. Here the authors investigate the circuit mechanism by which the subiculum contributes to initiation and propagation of hippocampal seizures in a mouse model.
- Fan Fei
- , Xia Wang
- & Yi Wang
-
Article
| Open AccessSingle residue modulators of amyloid formation in the N-terminal P1-region of α-synuclein
The authors of this work characterize the effect of amino acid substitution on α-synuclein (α-Syn) aggregation. Residues 38 and 42 (in addition to 39) within the P1 region of α-Syn affect amyloid formation. The effect of substitution at position 38 is dependent on the amino-acid introduced, suggesting that specific interactions control α -Syn aggregation.
- Sabine M. Ulamec
- , Roberto Maya-Martinez
- & David J. Brockwell
-
Article
| Open AccessEpigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology
Parkinson’s disease and dementia with Lewy bodies are closely related neurodegenerative disorders, although the epigenetic similarities are not well known. Here, the authors study Lewy pathology and DNA methylation in postmortem human frontal cortex, identifying differentially methylated genomic loci.
- Lasse Pihlstrøm
- , Gemma Shireby
- & Mathias Toft
-
Article
| Open AccessLysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models
Release of α-synuclein aggregates by neurons instigates spread of pathology in synucleinopathies, but the mechanism remains unclear. Here the authors show that neuronally generated α-synuclein aggregates accumulate within neuronal lysosomes and are released via SNARE-dependent lysosomal exocytosis.
- Ying Xue Xie
- , Nima N. Naseri
- & Manu Sharma
-
Article
| Open AccessMapping effective connectivity of human amygdala subdivisions with intracranial stimulation
The amygdala is known to be engaged in emotional and autonomic function, yet the detailed functional connectivity of the human amygdala remains unclear. Here, the authors examine effective connectivity in the amygdala of patients with epilepsy using direct focal electrical stimulation.
- Masahiro Sawada
- , Ralph Adolphs
- & Hiroyuki Oya
-
Article
| Open AccessPrimary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease
Here, the authors reveal using single-cell RNA sequencing that Parkinson’s disease (PD) patient-derived neuronal cells show altered primary cilia morphology and signaling suggesting cilia dysfunction may underlie PD pathogenesis.
- Sebastian Schmidt
- , Malte D. Luecken
- & Wolfgang Wurst
-
Article
| Open AccessThe causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization
Observational studies have found overlap between Alzheimer’s disease and other diseases and phenotypes, although the causal relationships are unclear. Here, the authors perform an age-stratified phenome-wide association study of Alzheimer’s disease (AD) genetic liability and follow-up Mendelian randomization analyses to examine whether these phenotypes have a causal effect on AD.
- Roxanna Korologou-Linden
- , Laxmi Bhatta
- & Neil M. Davies
-
Article
| Open AccessIdentification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT
Ayala Mariscal et al have identified and characterized the interface of pathogenic Huntingtin and the molecular chaperone DNAJB1. Histidine-244 of the C-terminal domain of DNAJB1 is a key residues for binding to the poly-proline region of HTT. This binding site is specific for the interaction with Huntingtin.
- S. M. Ayala Mariscal
- , M. L. Pigazzini
- & J. Kirstein
-
Article
| Open AccessLocal molecular and global connectomic contributions to cross-disorder cortical abnormalities
Changes to structural and functional connectivity can give rise to neurodegeneration and neurodevelopmental diseases. Here the authors investigate molecular and connectomic patterns in 13 different neurological, psychiatric and neurodevelopmental diseases from the ENIGMA consortium.
- Justine Y. Hansen
- , Golia Shafiei
- & Bratislav Misic
-
Article
| Open AccessRaptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex
Karalis et al show that genetic reduction of the mTORC1 component Raptor improves multiple phenotypes in mouse models of TSC. Their findings suggest that Raptor could be a potential therapeutic target for treating the neurological aspects of TSC.
- Vasiliki Karalis
- , Franklin Caval-Holme
- & Helen S. Bateup
-
Article
| Open AccessAβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy
Loss of excitatory synapses occur prior to the formation of amyloid plaques in Alzheimer’s disease. Here the authors show in an animal model that the loss of synapses induced by amyloid-beta oligomers requires over-activation of a stress-response pathway inducing structural remodelling of mitochondria in dendrites of cortical and hippocampal neurons.
- Annie Lee
- , Chandana Kondapalli
- & Franck Polleux
-
Article
| Open AccessHeparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology
The Cryo-EM structures reported in this work reveal how heparin incorporates into α-syn fibril formation to determine fibril polymorphs. This highlights the role of biological polymers in the conformational selection and neuropathological regulation of amyloid fibrils.
- Youqi Tao
- , Yunpeng Sun
- & Dan Li
-
Article
| Open AccessDisruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice
Pathologic oligomerization of hyper-phosphorylated Tau is a hallmark of tauopathies. Here the authors show that the loss of tubulin a4 polyglutamylation reverses tau hyperphosphorylation, oligomerization and microglia activation in a tauopathy mouse.
- Torben Johann Hausrat
- , Philipp C. Janiesch
- & Matthias Kneussel
-
Article
| Open Accessα-Synuclein fibril-specific nanobody reduces prion-like α-synuclein spreading in mice
Butler et al. selected disulfide bond-free nanobodies to target α-synuclein fibrils. Nanobody PFFNB2 was shown to disaggregate α-synuclein fibrils in vitro and inhibit α-synuclein pathology development in neuron cultures and mouse models.
- Yemima R. Butler
- , Yuqing Liu
- & Wenjing Wang
-
Comment
| Open AccessTiming is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain
Kv3 channels enable neurons to fire at very high frequencies (>100 Hz) which is fundamental to brain development and our ability to make sense of the world at large. Cryo-EM and structure-function studies by Chi et al. now uncover Kv3 channel gating mechanisms and support new precision medicine approaches for CNS diseases.
- Martin J. Gunthorpe
-
Article
| Open AccessCryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains
The authors report the near-atomic structure of the ex vivo aRML prion fibril. The comparison between this structure and the previously solved 263K prion fibril shows that both common and divergent features characterize these prion strains and their respective conformational replication templates.
- Forrest Hoyt
- , Heidi G. Standke
- & Allison Kraus
-
Article
| Open AccessCompulsive alcohol drinking in rodents is associated with altered representations of behavioral control and seeking in dorsal medial prefrontal cortex
Compulsive alcohol drinking is a core feature of alcohol use disorder. Here the authors find that in rodents, neural signals in a key decision-making brain region (dmPFC) shift from behavioral control to alcohol seeking during compulsive alcohol drinking behaviour.
- Nicholas M. Timme
- , Baofeng Ma
- & Christopher C. Lapish
-
Article
| Open AccessPattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2
Impaired sociability is often interpreted as social avoidance. Here, the authors show that the problem is actually failure to distinguish social from nonsocial stimuli, caused by indistinguishable coactivity patterns in the medial prefrontal cortex.
- Pan Xu
- , Yuanlei Yue
- & Hui Lu
-
Article
| Open AccessPeriarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer’s disease
The precise boundaries and flow compartments of perivascular spaces in the brain are incompletely understood. Here the authors show that pia is perforated and permissive to CSF flow, forming three types of perivascular spaces that remodel with age, with an abnormal type arising in Alzheimer’s disease and correlating with β-amyloid burden and differential macrophage uptake.
- Humberto Mestre
- , Natasha Verma
- & Rupal I. Mehta
-
Article
| Open AccessMyotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes
Myotonic dystrophy type 1 (DM1) is characterized by debilitating neurological symptoms. Dinca et al. demonstrate the pronounced impact of DM1 on the morphology and RNA metabolism of astrocytes. Their findings suggest astroglial pathology in DM1 brain dysfunction.
- Diana M. Dincã
- , Louison Lallemant
- & Mário Gomes-Pereira
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