Neurological disorders articles within Nature Communications

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  • Article
    | Open Access

    T cells from narcolepsy patients were recently reported to recognize hypocretin, a wakefulness-promoting neurohormone, suggesting autoimmune origin of the disease. Here the authors show that hypocretin-specific T cells expand both in healthy controls and in narcolepsy patients, and identify preliminary features that may distinguish them.

    • Wei Jiang
    • , James R. Birtley
    •  & Elizabeth D. Mellins

  • Article
    | Open Access

    The brain’s capacity to produce new neurons in response to injury is limited. Here, the authors transplant GABAergic progenitor cells and show that they synaptically incorporate into the damaged hippocampus and rescue memory problems and post-traumatic seizures caused by traumatic brain injury.

    • Bingyao Zhu
    • , Jisu Eom
    •  & Robert F. Hunt

  • Article
    | Open Access

    Familial cortical myoclonic tremor with epilepsy (FAME) is a slowly progressing cortical tremor mapping to various genomic loci, including intronic expansions in SAMD12 for FAME1. Here, Florian et al. describe mixed intronic TTTTA/TTTCA expansions of various lengths in the first intron of MARCH6 as a cause of FAME3.

    • Rahel T. Florian
    • , Florian Kraft
    •  & Christel Depienne

  • Article
    | Open Access

    Alzheimer’s disease is characterised by the deposition of Aβ amyloid fibrils and tau protein neurofibrillary tangles. Here the authors use cryo-EM to structurally characterise brain derived Aβ amyloid fibrils and find that they are polymorphic and right-hand twisted, which differs from in vitro generated Aβ fibrils.

    • Marius Kollmer
    • , William Close
    •  & Marcus Fändrich

  • Article
    | Open Access

    Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Here, authors report crystal structures of truncated human MFN2 in different nucleotide-loading states and show that MFN2 forms sustained dimers even after GTP hydrolysis.

    • Yu-Jie Li
    • , Yu-Lu Cao
    •  & Song Gao

  • Article
    | Open Access

    Deposition of tau protein aggregates occurs during aging and Alzheimer disease. Here, the authors show that tau burden in the anterior-temporal memory network is associated with disrupted fMRI connectivity and functional isolation of the hippocampus from other memory network components.

    • Theresa M. Harrison
    • , Anne Maass
    •  & William J. Jagust

  • Article
    | Open Access

    Food intake shapes intestinal microbiome composition, which in turn shapes adaptive immune responses. Here the authors show that dietary tryptophan restriction (DTR) protects mice from subsequent autoimmune neuropathology challenge by altering intestinal microbiota, highlighting the potential of diet-regulated microbiota to prevent immune pathology.

    • Jana K. Sonner
    • , Melanie Keil
    •  & Michael Platten

  • Article
    | Open Access

    Disturbances in IP3 receptor-mediated release of Ca2+ from the endoplasmatic reticulum are associated with neurodegenerative disease. Here, the authors identify in four families with hereditary spastic paraplegia biallelic mutations in RNF170 that associate with increased basal levels of IP3 receptors.

    • Matias Wagner
    • , Daniel P. S. Osborn
    •  & Rebecca Schüle

  • Article
    | Open Access

    Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

    • Hui Guo
    • , Elisa Bettella
    •  & Evan E. Eichler

  • Article
    | Open Access

    Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.

    • Eugene J. Gardner
    • , Elena Prigmore
    •  & Matthew E. Hurles

  • Article
    | Open Access

    How do diversity (entropy) and integration of activity across brain regions interact to support consciousness? Here the authors show that anaesthetised individuals and patients with disorders of consciousness exhibit overlapping reductions in both diversity and integration in the brain’s default mode network.

    • Andrea I. Luppi
    • , Michael M. Craig
    •  & Emmanuel A. Stamatakis

  • Article
    | Open Access

    Dystrophin-deficient mice are used to test corrective strategies for Duchenne muscular dystrophy, but evaluation of dystrophin expression requires collection of tissue samples from specific muscles and time points. Here, the authors generate mice in which dystrophin expression is coupled to luciferase, and show that bioluminescence allows non-invasive monitoring of dystrophin expression following genome editing.

    • Leonela Amoasii
    • , Hui Li
    •  & Eric N. Olson

  • Article
    | Open Access

    ABCC9 encodes the SUR2 subunit of KATP channels and dominant genetic variants in ABCC9 have been associated with cardiac phenotypes. Here, the authors report recessive ABCC9 mutations in individuals with mild intellectual disability, myopathy and cardiac systolic dysfunction which is associated with loss of KATP channel function.

    • Marie F. Smeland
    • , Conor McClenaghan
    •  & Gijs van Haaften

  • Article
    | Open Access

    MR-focused ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.

    • Agessandro Abrahao
    • , Ying Meng
    •  & Lorne Zinman

  • Article
    | Open Access

    Spinal and bulbar muscular atrophy is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor gene. Here the authors show that Src kinase signaling is activated in a mouse model of the disease, and that Src inhibition improves pathology and behavioral symptoms in mice.

    • Madoka Iida
    • , Kentaro Sahashi
    •  & Masahisa Katsuno

  • Article
    | Open Access

    The precise mechanisms that lead to medication-overuse headaches (MOH), which can occur with both over-the-counter and prescription pain-relief medicines, are still uncertain. In this study, authors show that the abnormal activation of dural nociceptor Nav1.9 channels by Nitric Oxide is responsible for triptan-induced MOH, causing hyperexcitability of dural nociceptors and headache.

    • Caroline Bonnet
    • , Jizhe Hao
    •  & Patrick Delmas

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here, authors show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity and can be targeted to rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion

    • Anthony Giampetruzzi
    • , Eric W. Danielson
    •  & Claudia Fallini

  • Article
    | Open Access

    A main symptom of chronic insufficient sleep is excessive daytime sleepiness. Here, Wang et al. report 42 genome-wide significant loci for self-reported daytime sleepiness in 452,071 individuals from the UK Biobank that cluster into two biological subtypes of either sleep propensity or sleep fragmentation.

    • Heming Wang
    • , Jacqueline M. Lane
    •  & Richa Saxena

  • Article
    | Open Access

    Hsp chaperones stabilize the inactive conformation of androgen receptor (AR) and are released upon hormone-induced AR activation. Here, the authors locate the Hsp binding region on AR, and show that Hsp70 reduces AR aggregation and promotes AR degradation in cellular and mouse models of a neuromuscular disorder.

    • Bahareh Eftekharzadeh
    • , Varuna C. Banduseela
    •  & Xavier Salvatella

  • Article
    | Open Access

    There are few studies of structural changes in ascending and descending sensorimotor pathways after stroke, beyond the corticospinal tract, in the brain. Here the authors identify changes in white matter structure in brainstem and spinal cord following stroke, and show its relationship to motor impairment.

    • Haleh Karbasforoushan
    • , Julien Cohen-Adad
    •  & Julius P. A. Dewald

  • Article
    | Open Access

    Memory is hypothesised to depend on different brain regions that interact in a network. Here, the authors use case studies of stroke patients with amnesia from the literature to identify brain regions that are part of this network.

    • Michael A. Ferguson
    • , Chun Lim
    •  & Michael D. Fox

  • Article
    | Open Access

    In patients with sporadic Alzheimer’s disease part of the Asp23 residues are isomerized to L-isoaspartate (L-isoAsp23). Here the authors present the MicroED structures of wild-type and L-isoAsp23 Aβ 20–34 amyloid fibrils that both form tightly packed cores and self-associate through two distinct interfaces with one of these interfaces being strengthened by the isoaspartyl modification.

    • Rebeccah A. Warmack
    • , David R. Boyer
    •  & Steven G. Clarke

  • Article
    | Open Access

    Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

    • Xiaopu Zhou
    • , Yu Chen
    •  & Nancy Y. Ip

  • Article
    | Open Access

    Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”

    • Vincenzo Salpietro
    • , Christine L. Dixon
    •  & Henry Houlden

  • Article
    | Open Access

    Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.

    • Jacob L. Taylor
    • , Jean-Christophe P. G. Debost
    •  & Elise B. Robinson

  • Article
    | Open Access

    Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.

    • C. F. Wright
    • , E. Prigmore
    •  & M. E. Hurles

  • Article
    | Open Access

    A number of therapeutic agents aimed at reducing pathology in Duchenne muscular dystrophy have been developed, but may have off-target effects when delivered systemically. Here, the authors express the therapeutic LIF transgene in leukocytes, and show this results in targeting to inflamed dystrophic muscle and reduced fibrosis by suppressing type 2 immunity.

    • Steven S. Welc
    • , Ivan Flores
    •  & James G. Tidball

  • Article
    | Open Access

    Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.

    • Atsushi Takata
    • , Mitsuko Nakashima
    •  & Naomichi Matsumoto

  • Article
    | Open Access

    Amyloid-β (Aβ) deposition occurs in Alzheimer's disease but its relation to disease features such as local brain hypometabolism or cognitive decline is unclear. Here, the authors show that Aβ aggregation in the brain’s default mode network leads to hypometabolism in distant but functionally connected areas.

    • Tharick A. Pascoal
    • , Sulantha Mathotaarachchi
    •  & Pedro Rosa-Neto

  • Article
    | Open Access

    Genome-wide association studies (GWAS) have so far uncovered more than 200 loci for multiple sclerosis (MS). Here, the authors integrate data from various sources for a cell type-specific pathway analysis of MS GWAS results that specifically highlights the involvement of the immune system in disease pathogenesis.

    • Lohith Madireddy
    • , Nikolaos A. Patsopoulos
    •  & Sergio E. Baranzini

  • Article
    | Open Access

    Monozygotic (MZ) twins are ideal to study the influence of non-genetic factors on complex phenotypes. Here, Souren et al. perform an EWAS in peripheral blood mononuclear cells from 45 MZ twins discordant for multiple sclerosis and identify disease and treatment-associated epigenetic markers.

    • Nicole Y. Souren
    • , Lisa A. Gerdes
    •  & Jörn Walter

  • Article
    | Open Access

    Here, using the EcoHIV mouse model of infection, Bertrand et al. report that HIV infection contributes to ischemic stroke damage and decreased tissue recovery by disrupting blood–brain barrier integrity and show that antivirals with high CNS penetration can reduce tissue injury and accelerate post-stroke recovery.

    • Luc Bertrand
    • , Fannie Méroth
    •  & Michal Toborek

  • Article
    | Open Access

    A key challenge is to find/re-purpose approved drugs that could be used in humans to induce autophagy-associated clearance of neurodegenerative proteins. Here, authors demonstrate that felodipine, an anti-hypertensive drug, can induce autophagy and clear a variety of aggregated neurodegenerative disease-associated proteins in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug.

    • Farah H. Siddiqi
    • , Fiona M. Menzies
    •  & David C. Rubinsztein

  • Article
    | Open Access

    Diagnosis and classification of peripheral neuropathy (PN) is facilitated by nerve conduction (NC) studies. Here, Bjornsdottir et al. find a low-frequency PRPH splice-donor variant that associates with NC amplitude and neurological assessment of recalled PRPH variant carriers reveals increased risk of a mild sensory-negative PN.

    • Gyda Bjornsdottir
    • , Erna V. Ivarsdottir
    •  & Kari Stefansson

  • Article
    | Open Access

    Following muscle damage, an inflammatory response is associated to activation of satellite cells, which drive muscle repair. Here, the authors show that upregulation of Zeb1 in macrophages and muscle fibres regulates inflammation, and also show a role for Zeb1 in maintenance of satellite cell quiescence.

    • Laura Siles
    • , Chiara Ninfali
    •  & Antonio Postigo

  • Article
    | Open Access

    Rapid arrival to hospital after stroke is critical for patients to receive effective treatment. Here, the authors examine how stroke patients’ social network structure relates to stroke arrival time, and show that small and close-knit personal networks predict delayed arrival.

    • Amar Dhand
    • , Douglas Luke
    •  & Jin-Moo Lee

  • Article
    | Open Access

    It is unclear if early pathological changes in normal-appearing multiple sclerosis (MS) tissue are reflected by molecular changes in microglia, which might contribute to lesion initiation. Here, authors demonstrate significant intrinsic differences in the human microglial transcriptome between grey and white matter regions, isolated from MS and non-neurological control donors, and show early microglial changes related to MS pathology.

    • Marlijn van der Poel
    • , Thomas Ulas
    •  & Inge Huitinga

  • Article
    | Open Access

    GWAS have identified over 41 susceptibility loci for Parkinson’s disease (PD). Here, the authors integrate PD GWAS summary statistics with transcriptome data from monocytes and DLFPC tissue in a TWAS approach and find 66 significant associations with PD risk highlighting lysosomal and innate immune functions.

    • Yang I. Li
    • , Garrett Wong
    •  & Towfique Raj

  • Article
    | Open Access

    A number of disease-causing human transthyretin (TTR) mutations are known to lead to amyloid formation. Here the authors combine neutron crystallography, native mass spectrometry and modelling studies to characterize the T119M and S52P-TTR mutants, providing mechanistic insights into TTR amyloidosis.

    • Ai Woon Yee
    • , Matteo Aldeghi
    •  & V. Trevor Forsyth

  • Article
    | Open Access

    Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.

    • Jennifer Friedman
    • , Desiree E. Smith
    •  & Joseph G. Gleeson

  • Article
    | Open Access

    tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.

    • Aleksandra Siekierska
    • , Hannah Stamberger
    •  & Peter De Jonghe

  • Article
    | Open Access

    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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