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Neuroscience

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Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome
Didier Dulon, … , Christine Petit, Aziz El-Amraoui
Didier Dulon, … , Christine Petit, Aziz El-Amraoui
Published July 9, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI94351.
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Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

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Abstract

Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total (Clrn1ex4–/–) and postnatal hair cell–specific conditional (Clrn1ex4fl/fl Myo15-Cre+/–) knockout mice. Clrn1ex4–/– mice were profoundly deaf, whereas Clrn1ex4fl/fl Myo15-Cre+/– mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and CaV1.3 Ca2+ channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic CaV1.3 Ca2+ channel complex via the Cavβ2 auxiliary subunit and the PDZ domain–containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus–mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in Clrn1ex4fl/fl Myo15-Cre+/– mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients.

Authors

Didier Dulon, Samantha Papal, Pranav Patni, Matteo Cortese, Philippe F.Y. Vincent, Margot Tertrais, Alice Emptoz, Aziz Tlili, Yohan Bouleau, Vincent Michel, Sedigheh Delmaghani, Alain Aghaie, Elise Pepermans, Olinda Allegria-Prevot, Omar Akil, Lawrence Lustig, Paul Avan, Saaid Safieddine, Christine Petit, Aziz El-Amraoui

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Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma
Behrouz Hassannia, … , Peter Vandenabeele, Tom Vanden Berghe
Behrouz Hassannia, … , Peter Vandenabeele, Tom Vanden Berghe
Published June 25, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI99032.
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Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma

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Abstract

High-risk neuroblastoma is a devastating malignancy with very limited therapeutic options. Here, we identify withaferin A (WA) as a natural ferroptosis-inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA dose-dependently either activates the nuclear factor–like 2 pathway through targeting of Kelch-like ECH-associated protein 1 (noncanonical ferroptosis induction) or inactivates glutathione peroxidase 4 (canonical ferroptosis induction). Noncanonical ferroptosis induction is characterized by an increase in intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which is sufficient to induce ferroptosis. This double-edged mechanism might explain the superior efficacy of WA as compared with etoposide or cisplatin in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing the growth and relapse rate of neuroblastoma xenografts. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced accumulation at the tumor site. Collectively, our data propose a novel therapeutic strategy to efficiently kill cancer cells by ferroptosis.

Authors

Behrouz Hassannia, Bartosz Wiernicki, Irina Ingold, Feng Qu, Simon Van Herck, Yulia Y. Tyurina, Hülya Bayır, Behnaz A. Abhari, Jose Pedro Friedmann Angeli, Sze Men Choi, Eline Meul, Karen Heyninck, Ken Declerck, Chandra Sekhar Chirumamilla, Maija Lahtela-Kakkonen, Guy Van Camp, Dmitri V. Krysko, Paul G. Ekert, Simone Fulda, Bruno G. De Geest, Marcus Conrad, Valerian E. Kagan, Wim Vanden Berghe, Peter Vandenabeele, Tom Vanden Berghe

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The COPII cargo adapter SEC24C is essential for neuronal homeostasis
Bo Wang, … , David Ginsburg, Mondira Kundu
Bo Wang, … , David Ginsburg, Mondira Kundu
Published June 25, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI98194.
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The COPII cargo adapter SEC24C is essential for neuronal homeostasis

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Abstract

SEC24 family members are components of the coat protein complex II (COPII) machinery that interact directly with cargo or with other adapters to ensure proper sorting of secretory cargo into COPII vesicles. SEC24C is 1 of 4 mammalian SEC24 paralogs (SEC24A–D), which segregate into 2 subfamilies on the basis of sequence homology (SEC24A/SEC24B and SEC24C/SEC24D). Here, we demonstrate that postmitotic neurons, unlike professional secretory cells in other tissues, are exquisitely sensitive to loss of SEC24C. Conditional KO of Sec24c in neural progenitors during embryogenesis caused perinatal mortality and microcephaly, with activation of the unfolded protein response and apoptotic cell death of postmitotic neurons in the murine cerebral cortex. The cell-autonomous function of SEC24C in postmitotic neurons was further highlighted by the loss of cell viability caused by disrupting Sec24c expression in forebrain neurons of mice postnatally and in differentiated neurons derived from human induced pluripotent stem cells. The neuronal cell death associated with Sec24c deficiency was rescued in knockin mice expressing Sec24d in place of Sec24c. These data suggest that SEC24C is a major cargo adapter for COPII-dependent transport in postmitotic neurons in developing and adult brains and that its functions overlap at least partially with those of SEC24D in mammals.

Authors

Bo Wang, Joung Hyuck Joo, Rebecca Mount, Brett J. W. Teubner, Alison Krenzer, Amber L. Ward, Viraj P. Ichhaporia, Elizabeth J. Adams, Rami Khoriaty, Samuel T. Peters, Shondra M. Pruett-Miller, Stanislav S. Zakharenko, David Ginsburg, Mondira Kundu

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Motivational valence is determined by striatal melanocortin 4 receptors
Anna Mathia Klawonn, … , Michael Michaelides, David Engblom
Anna Mathia Klawonn, … , Michael Michaelides, David Engblom
Published June 18, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI97854.
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Motivational valence is determined by striatal melanocortin 4 receptors

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Abstract

It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor–induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor–expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

Authors

Anna Mathia Klawonn, Michael Fritz, Anna Nilsson, Jordi Bonaventura, Kiseko Shionoya, Elahe Mirrasekhian, Urban Karlsson, Maarit Jaarola, Björn Granseth, Anders Blomqvist, Michael Michaelides, David Engblom

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Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity
Ming-Dong Zhang, … , Tibor Harkany, Tomas Hökfelt
Ming-Dong Zhang, … , Tibor Harkany, Tomas Hökfelt
Published June 12, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI120913.
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Ca2+-binding protein NECAB2 facilitates inflammatory pain hypersensitivity

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Abstract

Painful signals are transmitted by mutisynaptic glutamatergic pathways. Their first synapse between primary nociceptors and excitatory spinal interneurons gates sensory load. Glutamate release herein is orchestrated by Ca2+ sensor proteins with neuronal calcium-binding protein 2 (NECAB2) being particularly abundant. However, neither the importance of NECAB2+ neuronal contingents in dorsal root ganglia (DRG) and spinal cord nor function-determination by NECAB2 has been defined. A combination of histochemistry and single-cell RNA-seq showed NECAB2 in small/medium-sized C- and Aδ D-hair low threshold mechanoreceptors in DRG, as well as in protein kinase γ-positive excitatory spinal interneurons. NECAB2 was downregulated by peripheral nerve injury, offering the hypothesis that NECAB2 loss-of-funtion could limit pain sensation. Indeed, Necab2–/– mice reached a pain-free state significantly faster after peripheral inflammation than wild-type littermates. Genetic access to transiently-activated neurons revealed that a mediodorsal cohort of NECAB2+ neurons mediates inflammatory pain in mouse spinal dorsal horn. Here, besides dampening excitatory transmission in spinal interneurons, NECAB2 limited pronociceptive brain-derived neurotrophic factor release from sensory afferents. Hox8b-dependent reinstatement of NECAB2 expression in Necab2–/– mice then demonstrated that spinal/DRG NECAB2 alone could control inflammation-induced sensory hyperensitivity. Overall, we identify NECAB2 as a critical component of pro-nociceptive pain signaling whose inactivation offers substantial pain relief.

Authors

Ming-Dong Zhang, Jie Su, Csaba Adori, Valentina Cinquina, Katarzyna Malenczyk, Fatima Girach, Changgeng Peng, Patrik Ernfors, Peter Löw, Lotta Borgius, Ole Kiehn, Masahiko Watanabe, Mathias Uhlén, Nicholas Mitsios, Jan Mulder, Tibor Harkany, Tomas Hökfelt

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Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction
Samir R. Nath, … , David E. Housman, Andrew P. Lieberman
Samir R. Nath, … , David E. Housman, Andrew P. Lieberman
Published May 29, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI99042.
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Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

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Abstract

Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-Seq to identify pathways that are disrupted in diseased muscle using AR113Q knock-in mice. This analysis unexpectedly identified significantly diminished expression of numerous ubiquitin-proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age-, hormone- and glutamine length-dependent and arose due to a toxic gain-of-function conferred by the mutation. Moreover, altered gene expression was associated with decreased level of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder.

Authors

Samir R. Nath, Zhigang Yu, Theresa A. Gipson, Gregory B. Marsh, Eriko Yoshidome, Diane M. Robins, Sokol V. Todi, David E. Housman, Andrew P. Lieberman

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Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy
Théo Ribierre, … , Richard Miles, Stéphanie Baulac
Théo Ribierre, … , Richard Miles, Stéphanie Baulac
Published April 30, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI99384.
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Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy

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Abstract

DEP domain–containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid–sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit — brain somatic and germline — mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules.

Authors

Théo Ribierre, Charlotte Deleuze, Alexandre Bacq, Sara Baldassari, Elise Marsan, Mathilde Chipaux, Giuseppe Muraca, Delphine Roussel, Vincent Navarro, Eric Leguern, Richard Miles, Stéphanie Baulac

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Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress
Jaime N. Guzman, … , Paul T. Schumacker, D. James Surmeier
Jaime N. Guzman, … , Paul T. Schumacker, D. James Surmeier
Published April 30, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI95898.
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Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress

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Abstract

The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson’s disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass — demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well.

Authors

Jaime N. Guzman, Ema Ilijic, Ben Yang, Javier Sanchez-Padilla, David Wokosin, Dan Galtieri, Jyothisri Kondapalli, Paul T. Schumacker, D. James Surmeier

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Blocking p62/SQSTM1-dependent SMN degradation ameliorates Spinal Muscular Atrophy disease phenotypes
Natalia Rodriguez-Muela, … , Rajat Singh, Lee L. Rubin
Natalia Rodriguez-Muela, … , Rajat Singh, Lee L. Rubin
Published April 19, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI95231.
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Blocking p62/SQSTM1-dependent SMN degradation ameliorates Spinal Muscular Atrophy disease phenotypes

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Abstract

Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease caused by loss of functional SMN protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for SMA patients. The ubiquitin/proteasome system is known to regulate SMN protein levels; however whether autophagy controls SMN levels remains poorly explored. Here we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increase SMN levels, while induction of autophagy decreases SMN. SMN degradation occurs via its interaction with the autophagy adapter p62/SQSTM1. We also show that SMA neurons display reduced autophagosome clearance, increased p62/ubiquitinated protein levels, and hyperactivated mTORC1 signaling. Importantly, reducing p62 levels markedly increases SMN and its binding partner gemin2, promotes MN survival and extends lifespan in fly and mouse SMA models revealing p62 as a new potential therapeutic target to treat SMA.

Authors

Natalia Rodriguez-Muela, Andrey Parkhitko, Tobias Grass, Rebecca M. Gibbs, Erika M. Norabuena, Norbert Perrimon, Rajat Singh, Lee L. Rubin

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Insulin regulates astrocyte gliotransmission and modulates behavior
Weikang Cai, … , Emmanuel N. Pothos, C. Ronald Kahn
Weikang Cai, … , Emmanuel N. Pothos, C. Ronald Kahn
Published April 17, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI99366.
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Insulin regulates astrocyte gliotransmission and modulates behavior

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Abstract

Complications of diabetes affect tissues throughout body, including central nervous system. Epidemiological studies show that diabetic patients have increased risk of depression, anxiety, age-related cognitive decline and Alzheimer’s disease. Mice lacking insulin receptor in brain or on hypothalamic neurons display an array of metabolic abnormalities, however, the role of insulin action on astrocytes and neurobehaviors remains less well-studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogues could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity and other insulin resistant states.

Authors

Weikang Cai, Chang Xue, Masaji Sakaguchi, Masahiro Konishi, Alireza Shirazian, Heather A. Ferris, Mengyao Li, Ruichao Yu, Andre Kleinridders, Emmanuel N. Pothos, C. Ronald Kahn

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DREAM suppression in Huntington’s disease
José Naranjo and colleagues reveal that downregulation of DREAM mediates derepression of ATF6, and this elevation of ATF6 plays an early neuroprotective role in Huntington’s disease…
Published January 11, 2016
Scientific Show StopperNeuroscience
Thumb fig 6c unlabeled

Extra-cerebellar motor symptoms in Angelman’s syndrome
Caroline Bruinsma and colleagues evaluated cerebellar involvement in Angelman’s Syndrome motor deficits…
Published October 20, 2015
Scientific Show StopperNeuroscience
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An epigenetic intervention for neurodegenerative diseases
Eva Benito and colleagues demonstrate that SAHA, a histone-deacetylase inhibitor, improves spatial memory and selectively regulates the neuronal epigenome in a mouse model of neurodegeneration…
Published August 17, 2015
Scientific Show StopperNeuroscience
Thumb benito small

Genetic and environmental interactions in Parkinson’s disease
Alevtina Zharikov and colleagues reveal that interplay between α-synuclein and environmental toxin exposure influences parkinsonian neurodegeneration…
Published June 15, 2015
Scientific Show StopperNeuroscience
Thumb 64502 zharikov et al july c

TREM2 keeps myelinated axons under wraps
Pietro Poliani, Yaming Wang, and colleagues demonstrate that TREM2 deficiency reduces age-associated expansion of microglia and microglia-dependent remyelination…
Published April 20, 2015
Scientific Show StopperNeuroscience
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Synergy among Parkinson’s disease-associated genes
Durga Meka and colleagues demonstrate that crosstalk between parkin and RET maintains mitochondrial integrity and protects dopaminergic neurons…
Published March 30, 2015
Scientific Show StopperNeuroscience
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A model of periventricular leukomalacia
Tamar Licht, Talia Dor-Wollman and colleagues demonstrate that specific vulnerability of immature blood vessels surrounding ventricles predisposes to hypoxia-induced periventricular leukomalacia…
Published February 17, 2015
Scientific Show StopperNeuroscience
Thumb hp11 30015
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ISSN: 0021-9738 (print), 1558-8238 (online)

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