Reelin is a protein that is best known for its role in controlling neuronal layer formation in the developing cortex. Here, we studied its role for post‐natal cortical network function, which is ...poorly explored. To preclude early cortical migration defects caused by Reelin deficiency, we used a conditional Reelin knock‐out (RelncKO) mouse, and induced Reelin deficiency post‐natally. Induced Reelin deficiency caused hyperexcitability of the neocortical network in vitro and ex vivo. Blocking Reelin binding to its receptors ApoER2 and VLDLR resulted in a similar effect. Hyperexcitability in RelncKO organotypic slice cultures could be rescued by co‐culture with wild‐type organotypic slice cultures. Moreover, the GABAB receptor (GABABR) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABABRs in RelncKO mice. Immunolabeling of RelncKO cortical slices revealed a reduction in GABABR1 and GABABR2 surface expression at the plasma membrane and western blot of RelncKO cortical tissue revealed decreased phosphorylation of the GABABR2 subunit at serine 892 and increased phosphorylation at serine 783, reflecting receptor deactivation and proteolysis. These data show a role of Reelin in controlling early network activity, by modulating GABABR function.
Cover Image for this issue: https://doi.org/10.1111/jnc.15054.
We suggested the following modification of synaptic function after conditional Reelin knockout in the cerebral cortex: After Reelin deficiency, the pre‐synaptic reelin signaling cascade via the Reelin receptors ApoER2 and Vldlr and the adaptor protein Dab1, is no longer activated. This causes a decreased phosphorylation of pre‐synaptic GABAB receptors at S892, while phosphorylation at S783 increases, likely induced by AMP‐activated protein kinase (AMPK). As a consequence, GABAB receptors are degraded, calcium influx via NMDA receptors and synaptic vesicle release is increased. We believe that our findings revealed a new synaptic function of reelin expressed by cortical interneurons during cortical development.
Cover Image for this issue: https://doi.org/10.1111/jnc.15054.
There is increasing evidence from genetic, biochemical, pharmacological, neuroimaging and post-mortem studies that immunological dysregulation plays a crucial role in the pathogenesis of psychoses. ...The involvement of microglia in schizophrenia and bipolar disorder (BD) has remained controversial, however, since results from various post-mortem studies are still inconclusive. Here, we analyzed the estimated density of microglia of age-matched individuals with schizophrenia (
n
= 17), BD (
n
= 13), and non-psychiatric control subjects (
n
= 17) in the anterior midcingulate cortex (aMCC), a brain area putatively involved in the pathogenesis of psychoses, using ionized calcium binding adaptor molecule 1 (Iba1)—immunohistochemistry. The microglial cells displayed a homogenously distributed Iba1—staining pattern in the aMCC with slightly varying activation states in all three groups. The estimated microglial densities did not differ significantly between individuals with schizophrenia, BD and control subjects. Remarkably, when both hemispheres were investigated separately within the three groups, the density was significantly lateralized towards the right aMCC in schizophrenia (
p
= 0.01) and—even more evident—in BD subjects (
p
= 0.008). This left–right lateralization was not observed in the control group (
p
= 0.52). Of note, microglial density was significantly lower in BD individuals who did not commit suicide compared with BD individuals who died from suicide (
p
= 0.002). This difference was not observed between individuals with BD who committed suicide and controls. The results, tentatively interpreted, suggest a hitherto unknown increased lateralization of microglial density to the right hemisphere in both psychiatric groups. If confirmed in independent samples, lateralization should be considered in all post-mortem studies on microglia. Density differences between suicide and non-suicide individuals needs further elucidation.
Abstract
The expanded HTT CAG repeat causing Huntington’s disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately ...claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.
: Atopic dermatitis (AD) is a chronic skin disease affecting up to 15% of children in industrialized countries. AD belongs to the group of atopic disorders characterized by excessive immune ...reactions to ubiquitous antigens. Complex interactions between genetic and environmental factors have been suggested for atopic disorders. Dysregulation of the innate immune system appears crucial for the pathogenesis of AD. The NACHT‐LRRs (NLRs) represent a group of innate immune receptors with special relevance for inflammatory processes. In order to investigate the role of variation in NLR genes for AD, we genotyped 23 single nucleotide polymorphisms (SNPs) in seven selected NLR genes (CARD4, CARD15, CARD12, NALP1, NALP3, NALP12, MHC2TA) in 392 AD patients and 297 controls by restriction enzyme digestion or TaqMan assays. Single‐SNP analysis demonstrated significant associations of the CARD15_R702W variation and the NALP12_In9 T‐allele with AD (P = 0.008 and P = 0.03, resp.; insignificant after Bonferroni correction). In the CARD4 gene, a rare haplotype was more frequent in AD patients than in controls. Interactions between all pairs of SNPs in the seven genes were analysed by logistic regression. Significant interactions comprised SNPs in the CARD4 gene (CARD4_In1 and CARD4_Ex6, P = 6.56 × 10−7; CARD4_Prom und CARD4_Ex6, P = 2.45 × 10−4) and promoter polymorphisms in the CARD12 and NALP1 genes (P = 4.31 × 10−4). In conclusion, variation in individual genes from the NLR family as well as interactions within this group of innate immune receptor genes could play a role in AD pathogenesis. Investigations in other populations and functional studies are warranted to clarify contributions of NLR variation for this frequent skin disease.
Reelin is a protein that is best known for its role in controlling neuronal layer formation in the developing cortex. Here, we studied its role for post-natal cortical network function, which is ...poorly explored. To preclude early cortical migration defects caused by Reelin deficiency, we used a conditional Reelin knock-out (Reln
) mouse, and induced Reelin deficiency post-natally. Induced Reelin deficiency caused hyperexcitability of the neocortical network in vitro and ex vivo. Blocking Reelin binding to its receptors ApoER2 and VLDLR resulted in a similar effect. Hyperexcitability in Reln
organotypic slice cultures could be rescued by co-culture with wild-type organotypic slice cultures. Moreover, the GABA
receptor (GABA
R) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABA
Rs in Reln
mice. Immunolabeling of Reln
cortical slices revealed a reduction in GABA
R1 and GABA
R2 surface expression at the plasma membrane and western blot of Reln
cortical tissue revealed decreased phosphorylation of the GABA
R2 subunit at serine 892 and increased phosphorylation at serine 783, reflecting receptor deactivation and proteolysis. These data show a role of Reelin in controlling early network activity, by modulating GABA
R function. Cover Image for this issue: https://doi.org/10.1111/jnc.15054.
Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death ...are crucial in developing causal therapies. Here, we report that various disease‐associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP‐dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain‐containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease‐modifying strategies in proteinopathies.
Synopsis
Misfolded proteins recruit the linear ubiquitin chain assembly complex (LUBAC) via p97/VCP, resulting in the assembly of linear ubiquitin chains at protein aggregates, such as Huntingtin with an polyQ expansion (Htt‐polyQ). This modification interferes with proteotoxicity of Htt‐polyQ by preventing sequestration of the transcription factor Sp1 and by promoting proteasomal degradation of misfolded Htt‐polyQ.
The linear ubiquitin chain assembly complex (LUBAC) is recruited to misfolded protein species, such as mutant Huntingtin, Ataxin‐3, SOD1, and TDP‐43.
Linear ubiquitination of mutant Huntingtin causes remodeling of its interactive surface.
Expression of LUBAC is dysregulated in Huntington's disease by sequestration of the transcription factor Sp1 to misfolded Huntingtin.
Linear ubiquitination promotes removal of misfolded protein species in a p97/VCP‐ and proteasome‐dependent manner.
Recruitment of the LUBAC E3 ligase, best known for its function in NF‐κB signalling, to protein aggregates for linear ubiquitin‐mediated removal of misfolded neurodegenerative disease proteins such as huntingtin, SOD1 or TDP‐43 exemplifies a new, potentially targetable cellular mechanism for controlling proteinopathies.
Human cortical excitability can be modified by repetitive transcranial magnetic stimulation (rTMS), but the cellular mechanisms are largely unknown. Here, we show that the pattern of delivery of ...theta-burst stimulation (TBS) (continuous versus intermittent) differently modifies electric activity and protein expression in the rat neocortex. Intermittent TBS (iTBS), but not continuous TBS (cTBS), enhanced spontaneous neuronal firing and EEG gamma band power. Sensory evoked cortical inhibition increased only after iTBS, although both TBS protocols increased the first sensory response arising from the resting cortical state. Changes in the cortical expression of the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CB) indicate that changes in spontaneous and evoked cortical activity following rTMS are in part related to altered activity of inhibitory systems. By reducing PV expression in the fast-spiking interneurons, iTBS primarily affected the inhibitory control of pyramidal cell output activity, while cTBS, by reducing CB expression, more likely affected the dendritic integration of synaptic inputs controlled by other classes of inhibitory interneurons. Calretinin, the third major calcium-binding protein expressed by another class of interneurons was not affected at all. We conclude that different patterns of TBS modulate the activity of inhibitory cell classes differently, probably depending on the synaptic connectivity and the preferred discharge pattern of these inhibitory neurons.
Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha‐synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an ...A30P mutation carrier, we observed neuronal loss in the substantia nigra, locus coeruleus, and dorsal motor vagal nucleus, as well as widespread occurrence of alpha‐synuclein immunopositive Lewy bodies, Lewy neurites, and glial aggregates. Alpha‐synuclein aggregates ultrastructurally resembled Lewy bodies, and biochemical analyses disclosed a significant load of insoluble alpha‐synuclein, indicating neuropathological similarities between A30P disease patients and idiopathic PD, with a more severe neuropathology in A30P carriers. ANN NEUROL 2010;67:684–689
Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in ...the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and K(ATP) channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1(-/-) mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1(-/-) mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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