In this Issue


EphrinA/EphA-induced ectodomain shedding of neural cell adhesion molecule regulates growth cone repulsion through ADAM10 metalloprotease

PSA-NCAM and ephrinA/EphA3 coordinately regulate inhibitory synapse development. Here, we have found that ephrinA5 stimulates EphA3 kinase and ADAM10 activity to promote PSA-NCAM cleavage at a site in its second FNIII repeat, which regulates ephrinA5-induced growth cone collapse in GABAergic and non-GABAergic neurons. These findings identify a new regulatory mechanism which may contribute to inhibitory connectivity.

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Read the Editorial Highlight for this article on page 206. and the full article on page 267

Dynamin-2 in nervous system disorders

Disease-linked dynamin-2 mutations are mainly located in the middle and pleckstrin homology (PH) domains. (a) Dynamin is a multimodular enzyme comprising five highly conserved structural domains: a N-terminal GTPase domain (G-domain) required for binding and hydrolysis of GTP, a middle domain, a PH domain that mediates lipid interaction, a GTPase effector domain (GED) that regulates GTPase activity, which together with the middle domain is involved in dynamin oligomerization. Finally, a C-terminal proline rich domain (PRD) is present, which is required for interaction with SH3-domain-containing proteins. (b) A ‘T-shape’ dimer appears to be the structural unit of dynamin oligomers (Chappie et al. 2011). In this configuration, the PH domains (yellow) of neighboring monomers act as the ‘legs’ that insert dynamin into lipid membranes. Each ‘stalk’ region formed by the middle (green) and GED (red) domains interacts with the other in a crossed fashion, orienting the respective G-domains (blue) in opposite directions. Most of the mutations identified in CNM-patients (at the left) localize at the middle and C-terminal α-helix PH domains, both of which are implicated in dynamin oligomerization. Most of the CMT-linked mutations (at the right) clustering at the N-terminal region of the PH domain are involved in the insertion of dynamin into lipid membranes. Color code for structural domains and letters indicating the mutations are the same as those shown in A. In this diagram, PRD is omitted.

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Read the full article on page 210.

Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocain

We demonstrate tolerance to the neurochemical and behavioral effects of cocaine following extended-access cocaine self-administration. With respect to neurochemistry, we show reduced cocaine-induced dopamine uptake inhibition, an increased dose of cocaine required for 50% inhibition of the dopamine transporter, and reduced cocaine-induced dopamine overflow. In addition, we show escalation of cocaine intake and reduced cocaine-induced locomotor activity following cocaine self-administration.

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Read the full article on page 224.

The secretogranin II gene is a signal integrator of glutamate and dopamine inputs

We proposed hypothetical mechanism for the regulation of the secretogranin II gene as a signal integrator of glutamate and dopamine inputs. Glutamate or dopamine activates the Ca2+/MEK/ERK pathway, which thus contributes to the signal integration. Concurrently, activation of the PKA inhibitor KT5720-sensitive pathway by dopamine leads to accumulation of the repressor protein X that is otherwise susceptible to proteasome degradation. This repression system may determine the time window permissive to the cooperative activation by in-phase glutamate and dopamine inputs.

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Read the full article on page 233.

Nicotine induces dendritic spine remodeling in cultured hippocampal neurons

Activation of nicotinic acetylcholine receptors (nAChRs) in brain influences plasticity and cognition. Here, activation of α4β2* nAChRs, which are expressed on glutamatergic presynaptic termini, results in the enlargement of dendritic spines through the modulation of the glutamatergic neurotransmission. The remodeled spinal architecture might be responsible for the change in responsiveness of neural circuitry, leading to cholinergic tuning of brain function.

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Read the full article on page 246.

Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network

Celastrol, a plant-derived triterpene, has shown neuroprotective effects. However, little is known regarding the effect of celastrol on cadmium (Cd) neurotoxicity. This study underscores that celastrol prevents Cd-induced neuronal apoptosis via inhibiting activation of JNK (c-Jun N-terminal kinase) and Akt/mTOR network. Celastrol suppresses Cd-activated Akt/mTOR pathway by elevating PTEN (phosphatase and tensin homolog). The findings suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders.

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Read the full article on page 256.

Identification of two novel Shank3 transcripts in the developing mouse necrotex

SHANK3 is a synaptic scaffolding protein and is suspected of being implicated in the pathogenesis and neuropathology of ASD. We here identified two different amino-terminus truncated Shank3 transcripts, Shank3c-3 and Shank3c-4, expressed from the intron 10 of the Shank3 gene, and also suggested the epigenetic regulation of their expression via methyl CpG-binding protein 2 (MeCP2) that has been identified as the causative molecule of Rett syndrome.

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Read the full article on page 280.

Nucleic acid oxidation: an early feature of Alzheimer's disease

Levels of oxidized nucleic acids in nDNA and mtDNA were found to be significantly elevated in mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), late-stage AD (LAD), and a pooled diseased control group (DC) of frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) subjects compared to normal control (NC) subjects. Nucleic acid oxidation peaked early in disease progression and remained elevated. The study suggests nucleic acid oxidation is a general event in neurodegeneration.

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Read the full article on page 294.

Distinctive features of the D101N and D101G variants of superoxide dismutase 1; two mutations that produce rapidly progressing motor neuron disease

We sought to better characterize the biochemical features of two SOD1 mutants associated with rapidly progressing disease, the D101G and wild-type like D101N mutants. We observed using our cell model that that although similarities were observed when comparing the ability to bind metals and resist trypsin digestion, these mutants differed in their ability to initiate aggregation and to form the normal intramolecular disulfide bond. We conclude that these mutants exhibit distinct properties despite producing similar disease phenotypes in patients.

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Read the full article on page 305.

Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase

Regulation of phospho-ERK by STEP underlies important neuronal activities. A detailed enzymologic characterisation and cellular studies of STEP revealed that specific residues in KIM and active site mediated ERK recognition. Structural differences between the KIM-ERK interfaces and the active site among different ERK phosphatases could be targeted to develop specific STEP inhibitor, which has therapeutic potential for neurological disorders. PKA, protein kinase A & NGF, nerve growth factor.

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Read the full article on page 315.

Autosomal-dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter Aβ production

The amyloid precursor protein (APP) I716F mutation is associated with autosomal dominant Alzheimer's disease with the youngest age-at-onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer's disease mutations at the same codon (I716V and I716T), interfered distinctly with γ-secretase cleavage. While all three mutations direct γ-secretase cleavage towards the 48→38 production line, the APP I716F mutation also impaired the ε-cleavage and the fourth cleavage of γ-secretase, resembling a PSEN1 mutation. These features may contribute to the aggressiveness of this mutation.

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Read the full article on page 330.

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