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| Open AccessDesigner exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment
Exosomes function as intercellular information transmitters and are candidates for delivery of therapeutic agents. Here the authors present EXOtic, a synthetic biology device for in-situ production of designer exosomes and demonstrate in vivo application in models of Parkinson's disease.
- Ryosuke Kojima
- , Daniel Bojar
- & Martin Fussenegger
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Article
| Open AccessA comprehensive map coupling histone modifications with gene regulation in adult dopaminergic and serotonergic neurons
The limited size of some neuronal types and their entangled environment renders it difficult to study their transcription regulation. Here the authors present a comparative analysis of histone modifications and transcription in dopaminergic and serotonergic neurons and embryonic neural progenitors.
- Erik Södersten
- , Konstantinos Toskas
- & Johan Holmberg
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Article
| Open AccessNext generation histology methods for three-dimensional imaging of fresh and archival human brain tissues
Current available tissue clearing techniques are mostly used for rodent tissues. Here, the authors develop OPTIClear solution for fresh and archival human brain tissue clearing and establish associated protocols for three-dimensional histological investigations.
- Hei Ming Lai
- , Alan King Lun Liu
- & Steve M. Gentleman
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Article
| Open AccessEGFL7 reduces CNS inflammation in mouse
Endothelial cells release extracellular matrix components that regulate inflammation. Here the authors demonstrate that the extracellular matrix component epidermal growth factor-like protein 7 regulates inflammation in experimental autoimmune encephalomyelitis in the mouse.
- Catherine Larochelle
- , Timo Uphaus
- & Frauke Zipp
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| Open AccessImpaired β-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor
Dopamine receptor agonists are used for the treatment of various psychiatric diseases. Here, the authors screen approximately three million compounds and identify a novel class of D1R agonists that do not have a catechol scaffold and possess promising pharmacokinetic properties.
- David L. Gray
- , John A. Allen
- & Michael D. Ehlers
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Article
| Open AccessNeuropathic MORC2 mutations perturb GHKL ATPase dimerization dynamics and epigenetic silencing by multiple structural mechanisms
Microrchidia CW-type zinc finger protein 2 (MORC2) is an effector of epigenetic silencing by the human silencing hub (HUSH). Here the authors present the crystal structures of MORC2 and disease-causing MORC2 mutants and give mechanistic insights into how MORC2 mediates HUSH-dependent silencing.
- Christopher H. Douse
- , Stuart Bloor
- & Yorgo Modis
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Article
| Open AccessDirect effects of transcranial electric stimulation on brain circuits in rats and humans
Though transcranial electric stimulation has been used to influence brain activity, it is debated whether neuronal spiking activity is directly affected by commonly-used protocols. Here, the authors quantify the voltage gradients necessary to instantaneously affect neuronal spiking and show that they are higher than commonly-used protocols.
- Mihály Vöröslakos
- , Yuichi Takeuchi
- & Antal Berényi
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| Open AccessFasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling
Stimulant drugs are most commonly used to treat ADHD. Here, the authors demonstrate that in adolescents with ADHD who also have genetic variation in genes impacting metabotropic glutamate signaling, the non-stimulant mGluR activator fasoracetam is well tolerated and may be beneficial in alleviating symptoms of this disease.
- Josephine Elia
- , Grace Ungal
- & Hakon Hakonarson
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Article
| Open AccessCUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts
Repeat-associated non-AUG (RAN) translation contributes to the pathogenic mechanism of several microsatellite expansion diseases. Here the authors delineate the different steps involved in recruiting the ribosome to initiate G4C2 RAN translation to produce poly-Glycine Alanine, poly-Glycine Proline, and poly-Glycine Arginine repeats.
- Ricardos Tabet
- , Laure Schaeffer
- & Clotilde Lagier-Tourenne
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Article
| Open AccessPhf8 histone demethylase deficiency causes cognitive impairments through the mTOR pathway
Mutations in PHF8 gene are genetically associated with X-linked mental retardation. Here, Chen et al. show that Phf8 KO mouse have cognitive and synaptic plasticity impairment, and pharmacological inhibition of mTOR signaling can partially alleviate such defects.
- Xuemei Chen
- , Shuai Wang
- & Charlie Degui Chen
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Article
| Open AccessC9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation
Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors show that (GGGGCC) n translation can initiate without a 5′-cap, and this cap-independent translation is upregulated by stress mediated through eIF2α phosphorylation.
- Weiwei Cheng
- , Shaopeng Wang
- & Shuying Sun
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Article
| Open AccessLoss of mtDNA activates astrocytes and leads to spongiotic encephalopathy
Astrocytes in the brain are metabolically dynamic. Here, Ignatenko, Chilov and colleagues delete mitochondrial DNA (mtDNA) in a cell type specific manner, and show that inactivation of mtDNA helicase Twinkle in astrocytes leads to spongiotic encephalopathy.
- Olesia Ignatenko
- , Dmitri Chilov
- & Anu Suomalainen
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Article
| Open AccessNetwork connectivity determines cortical thinning in early Parkinson’s disease progression
In Parkinson’s disease (PD), neurodegeneration spreads from the brainstem to the cerebral cortex. Here, in a longitudinal study of PD patients, the authors found that cortical thinning followed neural connectivity from a “disease reservoir”.
- Y. Yau
- , Y. Zeighami
- & A. Dagher
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Article
| Open AccessSystematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic
Progressive multiple sclerosis is an inflammatory and degenerative disease of the central nervous system, for which effective treatment is lacking. The authors carry out a screen to identify orally available generic medications, and show that the antidepressant clomipramine reduces pathology in mouse models.
- Simon Faissner
- , Manoj Mishra
- & V. Wee Yong
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Article
| Open AccessEvidence for causal top-down frontal contributions to predictive processes in speech perception
The role of frontal lobes in speech perception is controversial. Here, the authors show that neurodegeneration of frontal speech regions delays prediction reconciliation in temporal cortex and results in inflexible prior expectations, indicating that fronto-temporal interactions determine predictive processes in speech.
- Thomas E. Cope
- , E. Sohoglu
- & James B. Rowe
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Article
| Open AccessDownregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches
Drugs targeting myostatin reverse muscle wasting in animal models, but have limited efficacy in patients. The authors show that the myostatin pathway is downregulated in patients, possibly explaining the poor outcome of anti-myostatin approaches, and that it can be reactivated by correcting disease-causing mutations in mice.
- Virginie Mariot
- , Romain Joubert
- & Julie Dumonceaux
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Article
| Open AccessRods progressively escape saturation to drive visual responses in daylight conditions
Rod photoreceptors are thought to be saturated under bright light. Here, the authors describe the physiological parameters that mediate response saturation of rod photoreceptors in mouse retina, and show that rods can drive visual responses in photopic conditions.
- Alexandra Tikidji-Hamburyan
- , Katja Reinhard
- & Thomas A. Münch
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Article
| Open AccessTranscriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis
CD4+ T cells secreting interleukin-17 (TH17) have diverse functions in modulating autoimmune diseases. Here the authors show via transcriptome analyses that a subset of human TH 17 co-expressing interferon-γ (TH1/17) has a molecular signature similar to “pathogenic” mouse TH 17 but distinct from “non-pathogenic” mouse TH 17.
- Dan Hu
- , Samuele Notarbartolo
- & Howard L. Weiner
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Article
| Open AccessGenome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus
Most SNPs are located in non-coding genomic regions and their function remains elusive. Here, the authors perform a genome-wide scan of expression and DNA methylation quantitative trait loci in human hippocampal tissue to provide a resource for the functional interpretation of SNPs in brain disorders.
- Herbert Schulz
- , Ann-Kathrin Ruppert
- & Sven Cichon
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| Open AccessSupramammillary glutamate neurons are a key node of the arousal system
Supramammillary nucleus (SuM) neurons have been studied in the context of REM sleep but their possible role in mediating wakefulness is not known. Here the authors elucidate the distinct functional contributions of three subpopulations in the SuM on electrographical and behavioral arousal in mice using genetically targeted approaches.
- Nigel P. Pedersen
- , Loris Ferrari
- & Patrick M. Fuller
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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 AccessCross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.
- Beben Benyamin
- , Ji He
- & Dongsheng Fan
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Article
| Open AccessNeutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage
Neutrophils are important modulators of tissue damage after intracerebral hemorrhage (ICH), but how this function is regulated is not clear. Here, the authors show interleukin-27 promotes the tissue-protecting functions of neutrophils via, at least partly, the induction of lactoferrin to present a potential therapy for ICH.
- Xiurong Zhao
- , Shun-Ming Ting
- & Jaroslaw Aronowski
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Article
| Open AccessMuscle pathology from stochastic low level DUX4 expression in an FSHD mouse model
Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Here, the authors generate a novel mouse model with titratable expression of DUX4, and show that it recapitulates several features of the human pathology.
- Darko Bosnakovski
- , Sunny S. K. Chan
- & Michael Kyba
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Article
| Open AccessAn injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling
The cystic cavity that develops following injuries to brain or spinal cord is a major obstacle. Here the authors show an injection of imidazole poly(organophosphazenes), a hydrogel with thermosensitive sol–gel transition behavior, almost completely eliminates cystic cavities in a clinically relevant rat spinal cord injury model.
- Le Thi Anh Hong
- , Young-Min Kim
- & Byung Gon Kim
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Article
| Open AccessThe non-coding RNA BC1 regulates experience-dependent structural plasticity and learning
Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors.
- Victor Briz
- , Leonardo Restivo
- & Claudia Bagni
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Article
| Open AccessMicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain
Dysregulation of voltage gated potassium channels is a feature of neuropathic pain. Here in a rat model the authors identify the microRNA cluster miR-17-92 as a regulator of voltage gated potassium channels in the dorsal root ganglion neurons.
- Atsushi Sakai
- , Fumihito Saitow
- & Hidenori Suzuki
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Article
| Open AccessAntisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice
X-linked myotubular myopathy is caused by mutations in the gene coding for myotubularin 1, and is characterized by overexpression of dynamin 2. Here the authors develop antisense oligonucleotides to dynamin 2, and show that systemic injection leads to improved pathology in mice.
- Hichem Tasfaout
- , Suzie Buono
- & Jocelyn Laporte
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Article
| Open AccessFetal and postnatal metal dysregulation in autism
The contribution of metal exposure to the etiology of ASD is unclear. Here the authors tested whether elemental dysregulation contributes to ASD risk by analysing tooth metal biomarkers from ASD discordant twins, and found significant differences in metal uptake between ASD cases and their control twin siblings, but only during certain developmental periods.
- Manish Arora
- , Abraham Reichenberg
- & Sven Bölte
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Article
| Open AccessLipoprotein-biomimetic nanostructure enables efficient targeting delivery of siRNA to Ras-activated glioblastoma cells via macropinocytosis
Drug delivery in brain tumours is still a significant clinical concern. In this study, the authors develop a biomimetic lipoprotein nanoparticle for the efficient delivery of ATF5 siRNA inRas-activated brain cancer cells, where the nanoparticle is internalized by macropinocytosis in a Ras-dependent manner.
- Jia-Lin Huang
- , Gan Jiang
- & Xiao-Ling Gao
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Article
| Open AccessProtein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy
Maternal diabetes can induce neural tube defects (NTD). Here, the authors show that in mice, deletion ofPrkca(encoding protein kinase C-alpha) restores autophagy, via suppression of miR-129-2 and reversal of reduced peroxisome proliferator-activated receptor c coactivator 1alpha, so reducing NTDs.
- Fang Wang
- , Cheng Xu
- & Peixin Yang
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Article
| Open AccessDiurnal and seasonal molecular rhythms in human neocortex and their relation to Alzheimer’s disease
Diurnal and seasonal rhythms modulate brain function, but we do not know the genomic basis for these rhythms. Here, Limet al. show diurnal and seasonal rhythms of gene expression in the human brain, their relationship to histone acetylation and DNA methylation, and their disruption in Alzheimer’s disease.
- Andrew S. P. Lim
- , Hans-Ulrich Klein
- & Philip L. De Jager
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Article
| Open AccessFaster phonological processing and right occipito-temporal coupling in deaf adults signal poor cochlear implant outcome
Cochlear implants have variable outcomes for adult deafness. Here the authors show that fast responses and specific recruitment of right temporal cortex on a simple visual rhyming task strongly predicts poor implant performance.
- Diane S. Lazard
- & Anne-Lise Giraud
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Article
| Open AccessGenetic correlation between amyotrophic lateral sclerosis and schizophrenia
Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
- Russell L. McLaughlin
- , Dick Schijven
- & Michael C. O’Donovan
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Article
| Open AccessDNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons
Transcriptional changes occur in the dorsal root ganglion in response to nerve injury and may contribute to neuropathic pain. Here the authors show that the DNA methyltransferase DNMT3a is upregulated in rodents following nerve injury, and may contribute to pain-like behaviour by decreasing expression of the voltage-gated potassium channel Kv1.2.
- Jian-Yuan Zhao
- , Lingli Liang
- & Yuan-Xiang Tao
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Article
| Open AccessTransient auditory nerve demyelination as a new mechanism for hidden hearing loss
Hidden hearing loss (HHL) is an auditory neuropathy that impairs one’s ability to hear, particularly in a noisy environment. Here the authors show that in mice, transient loss of cochlear Schwann cells results in permanent disruption of the cochlear heminodal structure, leading to auditory deficits characteristic of HHL.
- Guoqiang Wan
- & Gabriel Corfas
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Article
| Open AccessDysfunction of ventrolateral striatal dopamine receptor type 2-expressing medium spiny neurons impairs instrumental motivation
D2 receptor-expressing medium spiny neurons (D2-MSNs) are thought to suppress goal-directed behaviours. Here authors ablate D2-MSNs specifically in the ventrolateral striatum, and find that surprisingly, it leads to a reduction in goal-directed motivation in mice.
- Iku Tsutsui-Kimura
- , Hiroyuki Takiue
- & Kenji F. Tanaka
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Article
| Open AccessNovel genetic loci associated with hippocampal volume
The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.
- Derrek P. Hibar
- , Hieab H. H. Adams
- & M. Arfan Ikram
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Article
| Open AccessCCT complex restricts neuropathogenic protein aggregation via autophagy
The CCT complex, a key player in the chaperone machinery, has been implicated in Huntington’s disease. Pavelet al. show that CCT2/5/7 also play an essential role in autophagosome degradation, and that the aggregation of proteins upon CCT2/5/7 depletion is primarily a consequence of impaired autophagy.
- Mariana Pavel
- , Sara Imarisio
- & David C. Rubinsztein
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Article
| Open AccessStructural basis of myelin-associated glycoprotein adhesion and signalling
Myelin-associated glycoprotein (MAG) maintains myelin-axon spacing. Here, the authors report the crystal structures of the MAG full ectodomain in complex with oligosaccharide, and use additional assays to provide insights into the mechanism of MAG-mediated signalling.
- Matti F. Pronker
- , Suzanne Lemstra
- & Bert J. C. Janssen
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Article
| Open AccessCl-out is a novel cooperative optogenetic tool for extruding chloride from neurons
Chloride regulation is important for setting GABAergic reversal potential, though tools to manipulate chloride levels are limited. Here, the authors combine Archaerhodopsin with a chloride channel opsin to generate an optogenetic chloride extrusion strategy, ‘Cl-out’, which they demonstrate in hippocampal slices.
- Hannah Alfonsa
- , Jeremy H. Lakey
- & Andrew J. Trevelyan
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Article
| Open AccessBasal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology
Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.
- Taylor W. Schmitz
- , R. Nathan Spreng
- & Ansgar J. Furst
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Article
| Open AccessMonitoring peripheral nerve degeneration in ALS by label-free stimulated Raman scattering imaging
Sensitive and label-free imaging methods to visualize nerve degeneration are currently lacking. Here authors show that stimulated Raman scattering (SRS) microscopy can be used to monitor peripheral nerve degeneration in mouse models of amyotrophic lateral sclerosis (ALS) and in postmortem tissue from ALS patients.
- Feng Tian
- , Wenlong Yang
- & Kevin Eggan
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Article
| Open AccessInduced sensorimotor brain plasticity controls pain in phantom limb patients
Pain in a phantom limb after limb deafferentation may be due to maladaptive sensorimotor representation. Here the authors find that sensorimotor plasticity induced by BMI training with the phantom hand, contrary to expectation, increased pain while dissociating prosthetic movements from the phantom arm relieved the pain.
- Takufumi Yanagisawa
- , Ryohei Fukuma
- & Youichi Saitoh
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Article
| Open AccessSevere NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages
Human mutations in the NDE1 gene have been associated with cortical malformations and severe microcephaly. Here, the authors show in embryonic rat brains that NDE1-depleted neural progenitors arrest at three specific cell cycle stages before mitosis, resulting in a severe decrease in neurogenesis.
- David J. Doobin
- , Shahrnaz Kemal
- & Richard B. Vallee
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Article
| Open AccessRapid α-oligomer formation mediated by the Aβ C terminus initiates an amyloid assembly pathway
The elucidation of amyloid nucleation mechanisms remains challenging as early oligomeric intermediates are transient and difficult to distinguish. Here the authors use Aβ- polyglutamine hybrid peptides designed to slow and limit amyloid maturation to provide insights into the structures of Aβ self-assembly intermediates.
- Pinaki Misra
- , Ravindra Kodali
- & Ronald Wetzel
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Article
| Open AccessRegulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes
The molecular mechanisms regulating myelination are only partially understood. Here authors show that Tsc1ablation in oligodendrocyte lineage activates ER stress and apoptotic programs in mice, and that enhancing PERK-eIF2α signalling partially rescues the myelination defects in Tsc1 mutants.
- Minqing Jiang
- , Lei Liu
- & Q. Richard Lu
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Article
| Open AccessA peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries
Accurate treatment of traumatic brain injuries, a leading cause of neurological disability and death in young people, is hampered by poor accumulation of drugs in the brain. Here, the authors describe a tetrapeptide that can efficiently target brain injuries and deliver therapeutic or diagnostic payload.
- Aman P. Mann
- , Pablo Scodeller
- & Erkki Ruoslahti
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Article
| Open AccessHuman glia can both induce and rescue aspects of disease phenotype in Huntington disease
The contribution of glia to Huntington's disease is unclear. The authors show that human glial progenitor cells (GPCs) expressing mutant huntingtin impair motor performance when engrafted into wild type mice, and wild type human GPCs ameliorate disease phenotypes when engrafted into an HD mouse model.
- Abdellatif Benraiss
- , Su Wang
- & Steven A. Goldman