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| Open AccessRapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury
Matrix metalloproteinases (MMPs) released from infiltrating immune cells are a major contributor to blood-brain barrier (BBB) breakdown following stroke. Here, the authors identify an early, MMP-independent BBB breakdown mechanism caused by rapid cytoskeletal rearrangements in endothelial cells, which could be inhibited by ADF.
- Yejie Shi
- , Lili Zhang
- & Jun Chen
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Article
| Open AccessIntracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites
α-synuclein is a protein linked to the occurrence of Parkinson's disease. Here, the authors use time-resolved in-cell NMR spectroscopy to study the repair of methionine-oxidized α-synuclein by endogenous cellular enzymes.
- Andres Binolfi
- , Antonio Limatola
- & Philipp Selenko
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Article
| Open AccessImpairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease
PLA2g6 regulates store-operated Ca2+ entry and is linked to Parkinson’s disease. Here, Zhou et al find faulty PLA2g6-dependent Ca2+signaling in idiopathic PD patients, and show that its impairment triggers autophagic dysfunction and loss of dopaminergic neurons in a new PLA2g6 ex2KO mouse model.
- Qingde Zhou
- , Allen Yen
- & Victoria M. Bolotina
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Article
| Open AccessToxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups
Aggregation of microtubule associated protein tau is one of cause of neuronal loss in tauopathies including Alzheimer’s disease. Here, the authors show that compounds with a 1,2-dihydroxybenzene skeleton can modify cysteine residues in tau and block toxic tau aggregation.
- Yoshiyuki Soeda
- , Misato Yoshikawa
- & Akihiko Takashima
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Article
| Open AccessBasolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits
Drug seeking behaviour has habitual neural substrates. Here, Murray et al. show that the basolateral amygdala and central nucleus of the amygdala are necessary to recruit and maintain, respectively, the intrastriatal functional transition that underlies cocaine seeking habits.
- Jennifer E. Murray
- , Aude Belin-Rauscent
- & David Belin
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Article
| Open AccessEPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques
Amyloid-beta deposits are a pathological hallmark of Alzheimer’s disease, and have previously been targeted in immunisation therapies. Here, the authors show that oral administration of the small molecule EPPS reduces Aß plaque and oligomer load in APP/PS1 mice and improves learning and memory performance.
- Hye Yun Kim
- , Hyunjin Vincent Kim
- & YoungSoo Kim
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Article
| Open AccessEndogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7
Nav1.7 channels are known to regulate pain perception in humans and mice. Here, the authors provide evidence that Nav1.7 deletion leads to transcriptional upregulation of opioid peptides in sensory neurons, and that treatment with the opioid blocker naloxone helps reverse analgesia in mice and human Nav1.7 nulls.
- Michael S. Minett
- , Vanessa Pereira
- & John N. Wood
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Article
| Open AccessDICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression
DICER1 is required for the maturation of miRNAs which regulate expression of thousands of genes. Here the authors show significantly reduced levels of DICER1in individuals having post-traumatic stress disorder and comorbid depression suggestive of a role in the molecular mechanism of the condition.
- Aliza P. Wingo
- , Lynn M. Almli
- & Kerry J. Ressler
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Article
| Open AccessAβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease
Understanding how ß-amyloid contributes to synapse loss and dysfunction is a central goal of Alzheimer’s disease research. Here, Leshchyns’ka et al.identify a novel mechanism by which Aß disassembles hippocampal glutamatergic synapses via cleavage of a neural cell adhesion molecule 2 (NCAM2).
- Iryna Leshchyns’ka
- , Heng Tai Liew
- & Vladimir Sytnyk
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Article
| Open AccessTRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production
Attempts to treat Alzheimer's disease by targeting γ-secretase cleavage of APP into Aß have been unsuccessful, partially due to off-target effects. Here, the authors identify TRPC6 as a novel γ-secretase modulator, showing that it interacts with APP to regulate Aß levels while sparing Notch cleavage.
- Junfeng Wang
- , Rui Lu
- & Yizheng Wang
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Article |
The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis
Munc18-1 binds trans-SNARE complexes and promotes membrane fusion in vitro. Here the authors provide genetic evidence that this trans-SNARE-regulating function plays an essential role in synaptic releases in neurons, and show that this function is disrupted by a disease-causing Munc18-1 mutation.
- Chong Shen
- , Shailendra S. Rathore
- & Jingshi Shen
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Article
| Open AccessDelta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease
Age is the greatest risk factor for Alzheimer’s disease, yet how ageing regulates disease pathology is unclear. Here, the authors find that asparagine endopeptidase expression increases with age and cleaves APP, contributing to ß-amyloid production and cognitive defects in a transgenic mouse model.
- Zhentao Zhang
- , Mingke Song
- & Keqiang Ye
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Article
| Open AccessStructural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug
The leukotriene receptor antagonist montelukast is an anti-asthmatic drug. Here, the authors show that montelukast reduces neuroinflammation, promotes hippocampal neurogenesis and restores learning and memory in old rats suffering from ageing-associated cognitive dysfunction.
- Julia Marschallinger
- , Iris Schäffner
- & Ludwig Aigner
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Article
| Open AccessZinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1
Temporal lobe epilepsy can cause ionic imbalance in the brain and alter transcriptional activities. Here, van Loo et al.show that the increase in neuronal zinc following status epilepticus can induce transcriptional change via metal-regulatory transcription factor 1, and alter voltage-gated calcium channel CaV3.2 and intrinsic neuronal excitability.
- Karen M. J. van Loo
- , Christina Schaub
- & Albert J. Becker
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Article
| Open AccessNeuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain
In Alzheimer's disease, tau spreads throughout the brain, however the nature of the tau species propagating from one neuron to another is not known. Here, Takeda et al. identify a rare, high-molecular-weight tau as the primary species taken up and transferred between synaptically connected neurons.
- Shuko Takeda
- , Susanne Wegmann
- & Bradley T. Hyman
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Article
| Open AccessMembrane stiffening by STOML3 facilitates mechanosensation in sensory neurons
To maintain viability, cells must be able to sense and respond to mechanical stimuli. Here, Qi et al. show that the STOML3 protein acts in mechanosensation by binding cholesterol and regulating membrane stiffness which can in turn regulate ion flux through mechanosensitive channels.
- Yanmei Qi
- , Laura Andolfi
- & Jing Hu
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Article
| Open AccessNeuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors
Myelin regeneration can occur spontaneously in demyelinating diseases but the underlying mechanisms are incompletely understood. Here the authors show that neuronal activity and glutamatergic synapses instruct oligodendrocyte progenitor cells to differentiate into new myelinating oligodendrocytes.
- Hélène O. B. Gautier
- , Kimberley A. Evans
- & Ragnhildur T Káradóttir
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Article
| Open AccessAblation of hippocampal neurogenesis in mice impairs the response to stress during the dark cycle
Adult hippocampal neurogenesis is involved in the response to stress but whether it exerts a positive or negative effect remains unclear. Here the authors ablate hippocampal neurogenesis in mice and find that the effects on anxiety behaviour depend on the time of day, and that neurogenesis specifically impairs the response to stress during the dark cycle.
- Cheng-Yu Tsai
- , Ching-Yen Tsai
- & Guo-Jen Huang
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Article
| Open AccessMutations in SLC12A5 in epilepsy of infancy with migrating focal seizures
The potassium-chloride co-transporter, KCC2 is an essential component in maintaining a gradient for chloride ions in neurons. Here Stodberg and colleagues identify loss-of-function mutations in the encoding geneSLC12A5, which impair normal synaptic function associated with early-onset epilepsy.
- Tommy Stödberg
- , Amy McTague
- & Manju A. Kurian
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Article
| Open AccessLonger-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study
Long-chain omega-3 polyunsaturated fatty acids are essential for neural development and lack of these fatty acids has been implicated in a number of mental health conditions. Here the authors report the longer-term efficacy of a randomized, double-blind, placebo-controlled clinical trial assessing the effects of fish oil capsules in individuals at ultrahigh risk for psychosis.
- G. Paul Amminger
- , Miriam R. Schäfer
- & Patrick D. McGorry
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Article
| Open AccessCritical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke
The sphingolipid sphingosine-1-phosphate (S1P) plays a vital role in vascular homeostasis through the interaction with its receptors S1PR1-5. Here, by using genetic and pharmacological approaches, the authors show that S1PR2-mediated signaling is crucial for the disruption of cerebrovascular integrity and development of intracerebral haemorrhage in a mouse stroke model.
- Gab Seok Kim
- , Li Yang
- & Teresa Sanchez
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Article
| Open AccessDeactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety
The medial prefrontal cortex (mPFC) is implicated in pain regulation, yet the underlying mechanisms are poorly understood. Here the authors establish a critical role for mPFC in regulating pain sensation and pain-related anxiety, mediated by activation of the cyclin-dependent kinase 5 signalling pathway.
- Guo-Qiang Wang
- , Cheng Cen
- & Yun Wang
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Article
| Open AccessSUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation
Synapsins anchor synaptic vesicles (SVs) to the actin cytoskeleton to establish the reserve vesicle pool. Here Tanget al. show that SUMOylation of synapsin 1a enhances its interaction with SVs to promote efficient reclustering following stimulation, and a mutation linked to autism and epilepsy leads to defective SUMOylation.
- Leo T. -H. Tang
- , Tim J. Craig
- & Jeremy M. Henley
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Article
| Open AccessA novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking
Cue-based therapies for treating drug addiction have proven to be only partially effective. Here the authors demonstrate a new memory retrieval based treatment protocol for drug addiction that results in long-lasting inhibition of drug seeking behavior in rodents.
- Yi-xiao Luo
- , Yan-xue Xue
- & Lin Lu
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Article |
CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination
CEP63 is a centrosomal protein that is mutated in the microcephaly disease Seckel syndrome. Here the authors disrupt Cep63 in the mouse and find that neural progenitor cells undergo p53-dependent cell death, and uncover a role for CEP63 in ensuring correct meiotic recombination in male gametes.
- Marko Marjanović
- , Carlos Sánchez-Huertas
- & Travis H. Stracker
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Article
| Open AccessTrans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation
Zinc is a nutritional factor implicated in autism spectrum disorders (ASDs), but evidence for a strong association and linking mechanism is largely lacking. Here, the authors report that trans-synaptic zinc mobilization rapidly rescues social interaction in two independent mouse models of ASD.
- Eun-Jae Lee
- , Hyejin Lee
- & Eunjoon Kim
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Article |
Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal
Abstinent smokers experience affective withdrawal symptoms that contribute to relapse, yet the circuitry and mechanisms underlying these symptoms are unknown. Here the authors identify a critical role for a ventral tegmental area-habenula-interpeduncular circuit in nicotine withdrawal-induced anxiety.
- Rubing Zhao-Shea
- , Steven R. DeGroot
- & Andrew R. Tapper
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Article |
Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain
Phagocytic glia can internalize protein aggregates in vitro. Here Pearce et al. show in Drosophila that glia clear mutant huntingtin (Htt) aggregates in a scavenger receptor Draper-dependent manner in vivo, and that internalized Htt aggregates induce the prion-like conversion of wild-type Htt expressed in the glial cytoplasm.
- Margaret M. P. Pearce
- , Ellen J. Spartz
- & Ron R. Kopito
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Article |
The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome
Mutations in the gene encoding DJ-1 are associated with early-onset familial forms of Parkinson’s disease, and several different molecular functions have been attributed to this protein. Moscovitz et al.show that DJ-1 physically binds the 20S proteasome and inhibits its degradation activity.
- Oren Moscovitz
- , Gili Ben-Nissan
- & Michal Sharon
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Article
| Open AccessAberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline
Aberrant hippocampal neurogenesis often occurs after acute seizures that produce epilepsy and cognitive impairment but the role of neurogenesis in the development of epilepsy is unclear. Here the authors suppress adult neurogenesis in mice preceding seizures and show that it reduces subsequent chronic seizure frequency and epilepsy-associated cognitive decline.
- Kyung-Ok Cho
- , Zane R. Lybrand
- & Jenny Hsieh
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Article |
Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells
Applications of human pluripotent stem cells (hPSCs) for disease modelling or cell therapy are hindered by low efficiency and heterogeneity of target cell types differentiated from hPSCs, such as motor neurons (MNs). Here the authors develop a method to derive highly pure motor neuron progenitor populations from human embryonic and induced pluripotent stem cells that yield functional MNs.
- Zhong-Wei Du
- , Hong Chen
- & Su-Chun Zhang
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Article
| Open AccessSynaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity
Membrane depolarization during increased neuronal activity as seen during epilepsy has been suggested to easily reverse neuronal GABA transporters. Here the authors use modelling and experimental data and challenge this view by showing that synaptic GABA release during excessive neuronal firing averts reversal of GABA uptake.
- Leonid Savtchenko
- , Maria Megalogeni
- & Ivan Pavlov
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Article
| Open AccessThe HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia
The targeting of inflammation has emerged as a promising therapeutic strategy for cerebral ischaemia. Here the authors show that TIM-3, a member of the T-cell immunoglobulin and mucin domain protein family, is upregulated in glial cells and plays a role in inflammation-associated brain injury under hypoxic conditions.
- Han Seok Koh
- , Chi Young Chang
- & Eun Jung Park
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Article
| Open AccessThe autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment
Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.
- Justin Cotney
- , Rebecca A. Muhle
- & James P. Noonan
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Article |
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
In Alzheimer’s disease (AD), β-amyloid plaques are tightly enveloped by microglia but the significance of this phenomenon is unknown. Here the authors used confocal and in vivotwo-photon imaging in AD mouse models and revealed that microglia constitute a barrier that seems to prevent the formation of neurotoxic hotspots of protofibrillar β-amyloid.
- Carlo Condello
- , Peng Yuan
- & Jaime Grutzendler
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Article
| Open AccessNew loci and coding variants confer risk for age-related macular degeneration in East Asians
Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Here, the authors carry out a two-stage genome-wide association study for AMD and identify three new AMD risk loci, highlighting the shared and distinct genetic basis of the disease in East Asians and Europeans.
- Ching-Yu Cheng
- , Kenji Yamashiro
- & Chiea Chuen Khor
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Article |
ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP
Dominant mutations in the RNA-binding protein FUS/TLS cause amyotrophic lateral sclerosis (ALS), an adult-onset motor neuron degenerative disease. Here, the authors show that ALS-causative FUS/TLS mutations directly bind the SMN and U1-snRNP complexes, producing both loss and gain of function effects on RNA processing.
- Shuying Sun
- , Shuo-Chien Ling
- & Don W. Cleveland
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Article |
Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus
Neurological disorders such as temporal lobe epilepsy (TLE) are known to be regulated by gene networks. In this study, the authors describe a genome-wide approach that uses samples of hippocampal tissue from patients with TLE, to identify the gene Sestrin 3 (SESN3) as a positive regulator of the disease.
- Michael R. Johnson
- , Jacques Behmoaras
- & Enrico Petretto
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Article
| Open AccessHuman iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects spinal cord motor neurons. Here the authors use induced pluripotent stem cell-derived motor neurons obtained from patients with ALS-linked mutations, and find functional deficits resulting from a progressive decrease in voltage-activated Na+ and K+currents that occur in the absence of cell death.
- Anna-Claire Devlin
- , Karen Burr
- & Gareth B. Miles
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Article |
An acetylation switch controls TDP-43 function and aggregation propensity
The nuclear protein TDP-43 is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Here, Cohen et al. discover lysine acetylation as a modification that regulates TDP-43 function, providing a mechanism that could be implicated in the pathogenesis of TDP-43 proteinopathies.
- Todd J. Cohen
- , Andrew W. Hwang
- & Virginia M. Y. Lee
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Article |
Small molecule-mediated stabilization of vesicle-associated helical α-synuclein inhibits pathogenic misfolding and aggregation
Small molecules that inhibit α-synuclein misfolding may have potential in the treatment of Parkinson’s disease. Fonseca-Ornelas et al.show that several of these molecules fail to block misfolding in the presence of membrane vesicles, and reveal how phtalocyanine tetrasulfonate, in contrast, overcomes this effect.
- Luis Fonseca-Ornelas
- , Sybille E. Eisbach
- & Markus Zweckstetter
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Article
| Open AccessEpigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance
Histone modification is critical for gene expression regulation during development. Here, the authors show that the demethylase LSD1 and its target gene ATN1are responsible for maintenance of neural progenitor cells during mouse cortical development.
- Feng Zhang
- , Dan Xu
- & Zhiheng Xu
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Article
| Open AccessActivated astrocytes enhance the dopaminergic differentiation of stem cells and promote brain repair through bFGF
In the adult brain, the neurotrophic factor basic fibroblast growth factor (bFGF) is predominantly secreted by astrocytes. Here the authors use optogenetics to activate astrocytes, leading to release of bFGF, inducing enhanced dopaminergic differentiation of neural progenitors and promoting brain repair in a mouse Parkinson’s disease model.
- Fan Yang
- , Yunhui Liu
- & Liping Wang
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Article |
Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7
The kinase LRRK2 is implicated in Parkinson’s disease progression and is known to be phosphorylated. Chia et al.show that this phosphorylation is mediated by the kinase CK1a, and is required for the recruitment of LRRK2 to Golgi-derived vesicles, suggesting a role for this protein in Golgi maintenance.
- Ruth Chia
- , Sara Haddock
- & Mark R. Cookson
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Review Article |
The role of protein clearance mechanisms in organismal ageing and age-related diseases
Proteins are subject to continuous and complex quality-control mechanisms, which ensure integrity of the proteome. Vilchez et al.review how a demise in these processes, collectively referred to as proteostasis, is linked to organismal ageing and the development of age-associated diseases.
- David Vilchez
- , Isabel Saez
- & Andrew Dillin
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Article |
Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism
Impairments of cerebellar-dependent motor control and learning are implicated in some forms of autism spectrum disorder (ASD). In this study, the authors provide a characterization of the motor deficits and cerebellar function abnormalities in a transgenic mouse model of ASD.
- Claire Piochon
- , Alexander D. Kloth
- & Christian Hansel
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Article
| Open AccessPathological roles of the VEGF/SphK pathway in Niemann–Pick type C neurons
Sphingosine is abnormally accumulated in Niemann–Pick type C disease (NP–C), but the causes of this accumulation have not been fully characterized. Here the authors show that sphingosine kinase activity is reduced in NP–C patient fibroblasts and NP–C mouse neurons due to defective vascular endothelial growth factor levels, suggesting therapeutic avenues.
- Hyun Lee
- , Jong Kil Lee
- & Hee Kyung Jin
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Article |
Recurrent de novo mutations implicate novel genes underlying simplex autism risk
Autism spectrum disorder (ASD) is a common disorder with a strong and complex genetic component. Here, the authors resequence 64 candidate neurodevelopmental disorder risk genes in almost 6,000 samples and identify novel genes associated with ASD.
- B. J. O'Roak
- , H. A. Stessman
- & E. E. Eichler
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Article |
Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model
Astrocytic network alterations are seen in Alzheimer’s disease (AD) but the underlying mechanisms have remained undefined. Here the authors use in vivomulitphoton microscopy to monitor spontaneous network activity of astrocytes in a mouse model of AD, and find that astroglial hyperactivity was largely mediated by activation of the purinergic receptor P2Y1.
- Andrea Delekate
- , Martina Füchtemeier
- & Gabor C. Petzold
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