neurogenpapers

[neurogenpapers]

Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance.

PubMed: Related Articles Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance. Neurosci Lett. 2017 Feb 24;: Authors: Lillenes MS, Støen M, Günther CC, Selnes P, Stenset VT, Espeseth T, Reinvang I, Fladby T, Tønjum T Abstract Mitochondrial dysfunction and DNA damage is intimately connected to ageing and neurodegeneration, including Alzheimer's disease (AD). A particular culprit in this context is oxidative stress, which is a result of increased reactive oxygen species (ROS) due to hyperactive or dysfunctional mitochondria and/or reduced DNA repair capacity. Base excision repair (BER) is the major pathway for repairing oxidative damage events in chromosomal and mitochondrial DNA. Defects in BER have been detected in ageing and neurodegeneration. Mitochondrial transcription factor A (TFAM) plays an important role in the maintenance of mitochondrial DNA integrity. The present study investigated single nucleotide polymorphisms (SNPs) in the genes encoding the BER components MutYH, OGG1, APE1, PolB and PolG and the gene encoding mitochondrial TFAM in a cohort of 161 AD patients, 96 non-AD patient controls (PC) and 192 healthy controls (HC). Notably, the minor allele carriers of APE1 rs1130409 and the common allele carriers of TFAM rs1937 were associated with reduced mini-mental state examination score in AD patients, PC and HC, with no distinction of SNP frequencies in either of these sub-groups. Collectively, the results suggest an association between DNA maintenance and decline in cognitive function. These studies enlighten the normal brain aging process and point to potential new biomarkers for cognitive function and impairment. PMID: 28242328 [PubMed - as supplied by publisher] http://dlvr.it/NWKx83

[neurogenpapers]

C. elegans as a model system to accelerate discovery for Parkinson disease.

PubMed: Related Articles C. elegans as a model system to accelerate discovery for Parkinson disease. Curr Opin Genet Dev. 2017 Feb 24;44:102-109 Authors: Martinez BA, Caldwell KA, Caldwell GA Abstract The nematode Caenorhabditis elegans possesses a wealth of opportunities to explore mechanisms which regulate metazoan complexity, basic cellular biology, and neuronal system attributes. Together, these provide a basis for tenable understanding of neurodegenerative disorders such as Parkinson disease (PD) through functional genomic analysis and pharmacological manipulation for the discovery of previously unknown genetic and environmental risk factors. The application of C. elegans has proven prescient in terms of the elucidation of functional effectors of cellular mechanisms underlying PD that translate to mammals. The current state of PD research using C. elegans encompasses defining obscure combinatorial interactions between genes or between genes and the environment, and continues to provide opportunities for the discovery of new therapeutic targets and disease-modifying drugs. PMID: 28242493 [PubMed - as supplied by publisher] http://dlvr.it/NWKLn4

[neurogenpapers]

Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer's disease mice.

PubMed: Related Articles Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer's disease mice. Blood. 2017 Feb 27;: Authors: Chen ZL, Revenko AS, Singh P, MacLeod AR, Norris EH, Strickland S Abstract Vascular abnormalities and inflammation are found in many Alzheimer's disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII-initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high molecular weight kininogen (HK), a marker for the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that the FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment. PMID: 28242605 [PubMed - as supplied by publisher] http://dlvr.it/NWJlqJ

[neurogenpapers]

Discovery and reporting of clinically-relevant germline variants in advanced cancer patients assessed using whole-exome sequencing

Preprint: Purpose: In precision cancer care, WES-based analysis of tumor-normal samples helps reveal somatic alterations but can also identify cancer-associated germline variants important for disease surveillance, treatment choice and cancer prevention. WES can also identify germline secondary findings impacting risk of cardiac, neurodegenerative or metabolic diseases. In patients with advanced cancer, the frequency of reportable secondary findings encountered with WES is not well defined. Methods: To address this question, we analyzed a cohort of 343 patients with advanced, metastatic cancer for whom we have performed tumor and germline WES interrogating more than 21,000 genes using a CLIA/CLEP approved assay. Results: 17% of patients in our cohort have one or more reportable germline variants, including patients with pathogenic variants in the BRCA1 and BRCA2 genes. The frequency of non-cancer clinically relevant germline variants (8.8%) was within the range of two control non-cancer cohorts (11.0% and 6.5%). The frequency of variants in cancer-associated genes was significantly higher (p http://dlvr.it/NWJf5v

[neurogenpapers]

TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement.

PubMed: Related Articles TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement. J Cell Biol. 2017 Feb 27;: Authors: Saunders CA, Harris NJ, Willey PT, Woolums BM, Wang Y, McQuown AJ, Schoenhofen A, Worman HJ, Dauer WT, Gundersen GG, Luxton GW Abstract The nucleus is positioned toward the rear of most migratory cells. In fibroblasts and myoblasts polarizing for migration, retrograde actin flow moves the nucleus rearward, resulting in the orientation of the centrosome in the direction of migration. In this study, we report that the nuclear envelope-localized AAA+ (ATPase associated with various cellular activities) torsinA (TA) and its activator, the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1), are required for rearward nuclear movement during centrosome orientation in migrating fibroblasts. Both TA and LAP1 contributed to the assembly of transmembrane actin-associated nuclear (TAN) lines, which couple the nucleus to dorsal perinuclear actin cables undergoing retrograde flow. In addition, TA localized to TAN lines and was necessary for the proper mobility of EGFP-mini-nesprin-2G, a functional TAN line reporter construct, within the nuclear envelope. Furthermore, TA and LAP1 were indispensable for the retrograde flow of dorsal perinuclear actin cables, supporting the recently proposed function for the nucleus in spatially organizing actin flow and cytoplasmic polarity. Collectively, these results identify TA as a key regulator of actin-dependent rearward nuclear movement during centrosome orientation. PMID: 28242745 [PubMed - as supplied by publisher] http://dlvr.it/NWJ8PL

[neurogenpapers]

Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium.

PubMed: Related Articles Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. Mol Psychiatry. 2017 Feb 28;: Authors: Stern S, Santos R, Marchetto MC, Mendes AP, Rouleau GA, Biesmans S, Wang QW, Yao J, Charnay P, Bang AG, Alda M, Gage FH Abstract Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.Molecular Psychiatry advance online publication, 28 February 2017; doi:10.1038/mp.2016.260. PMID: 28242870 [PubMed - as supplied by publisher] http://dlvr.it/NWHWbb

[neurogenpapers]

A case of possibly pathogenic PSEN2 R62C mutation in a patient with probable early-onset Alzheimer's dementia supported by structure prediction.

PubMed: Related Articles A case of possibly pathogenic PSEN2 R62C mutation in a patient with probable early-onset Alzheimer's dementia supported by structure prediction. Clin Interv Aging. 2017;12:367-375 Authors: Park KW, An SS, Bagyinszky E, Kim S Abstract A 49-year-old Korean male patient with dementia was diagnosed with probable early-onset Alzheimer's disease (AD). He presented with memory problems, personality changes, and disorientation. His family history of dementia was probably negative, since no family member with dementia was found or mentioned. Mild cortical atrophy was observed upon magnetic resonance imaging analyses of his brain, and the single-photon emission computed tomography analysis revealed hypoperfusion in the frontal, temporal, and limbic lobes. The patient was tested for mutations in APP, PSEN1, PSEN2, PGRN, MAPT, and PRNP genes. Genetic analysis revealed R62C mutation in PSEN2 gene. PSEN2 R62C mutation was previously reported in European populations, including Dutch and Belgian families with AD. Herein, we present the first case report of PSEN2 R62C mutation in Asia. PolyPhen-2 and SIFT software analyses predicted this mutation as "possibly damaging", suggesting its potential involvement with AD. In silico protein structural prediction analyses of PSEN2 R62 and C62 revealed two divergent structures, suggesting that large perturbations of R62C mutation might cause dysfunctions of PSEN2, which may alter the normal amyloid production. PMID: 28243073 [PubMed - in process] http://dlvr.it/NWGvsy

[neurogenpapers]

Mitochondrial diseases: advances and issues.

PubMed: Related Articles Mitochondrial diseases: advances and issues. Appl Clin Genet. 2017;10:21-26 Authors: Scarpelli M, Todeschini A, Volonghi I, Padovani A, Filosto M Abstract Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders caused by a dysfunction of the mitochondrial respiratory chain. They can be related to mutation of genes encoded using either nuclear DNA or mitochondrial DNA. The advent of next generation sequencing and whole exome sequencing in studying the molecular bases of MDs will bring about a revolution in the field of mitochondrial medicine, also opening the possibility of better defining pathogenic mechanisms and developing novel therapeutic approaches for these devastating disorders. The canonical rules of mitochondrial medicine remain milestones, but novel issues have been raised following the use of advanced diagnostic technologies. Rigorous validation of the novel mutations detected using deep sequencing in patients with suspected MD, and a clear definition of the natural history, outcome measures, and biomarkers that could be usefully adopted in clinical trials, are mandatory goals for the scientific community. Today, therapy is often inadequate and mostly palliative. However, important advances have been made in treating some clinical entities, eg, mitochondrial neuro-gastrointestinal encephalomyopathy, for which approaches using allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy have recently been developed. Promising new treatment methods are being identified so that researchers, clinicians, and patients can join forces to change the history of these untreatable disorders. PMID: 28243136 [PubMed] http://dlvr.it/NWGBKD

[neurogenpapers]

The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD.

PubMed: Related Articles The Role of Dipeptide Repeats in C9ORF72-Related ALS-FTD. Front Mol Neurosci. 2017;10:35 Authors: Freibaum BD, Taylor JP Abstract Expansion of a hexanucleotide (GGGGCC) repeat in the gene chromosome 9 open reading frame 72 (C9ORF72) is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). Three non-exclusive mechanisms have been proposed to contribute to the pathology initiated by this genetic insult. First, it was suggested that decreased expression of the C9orf72 protein product may contribute to disease. Second, the recognition that C9ORF72-related disease is associated with accumulation of GGGGCC repeat-containing RNA in nuclear foci led to the suggestion that toxic gain of RNA function, perhaps related to sequestration of RNA-binding proteins, might be an important driver of disease. Third, it was subsequently appreciated that GGGGCC repeat-containing RNA undergoes unconventional translation to produce unnatural dipeptide repeat (DPR) proteins that accumulate in patient brain early in disease. DPRs translated from all six reading frames in either the sense or antisense direction of the hexanucleotide repeat result in the expression of five DPRs: glycine-alanine (GA), glycine-arginine (GR), proline-alanine (PA), proline-arginine (PR) and glycine-proline (GP; GP is generated from both the sense and antisense reading frames). However, the relative contribution of each DPR to disease pathogenesis remains unclear. Here, we review evidence for the contribution of each specific DPR to pathogenesis and examine the probable mechanisms through which these DPRs induce neurodegeneration. We also consider the association of the toxic DPRs with impaired RNA metabolism and alterations to the liquid-like state of non-membrane-bound organelles. PMID: 28243191 [PubMed - in process] http://dlvr.it/NWFW6L

[neurogenpapers]

Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation.

PubMed: Related Articles Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation. Front Cell Neurosci. 2017;11:24 Authors: Jäkel S, Dimou L Abstract Glial cells, consisting of microglia, astrocytes, and oligodendrocyte lineage cells as their major components, constitute a large fraction of the mammalian brain. Originally considered as purely non-functional glue for neurons, decades of research have highlighted the importance as well as further functions of glial cells. Although many aspects of these cells are well characterized nowadays, the functions of the different glial populations in the brain under both physiological and pathological conditions remain, at least to a certain extent, unresolved. To tackle these important questions, a broad range of depletion approaches have been developed in which microglia, astrocytes, or oligodendrocyte lineage cells (i.e., NG2-glia and oligodendrocytes) are specifically ablated from the adult brain network with a subsequent analysis of the consequences. As the different glial populations are very heterogeneous, it is imperative to specifically ablate single cell populations instead of inducing cell death in all glial cells in general. Thanks to modern genetic manipulation methods, the approaches can now directly be targeted to the cell type of interest making the ablation more specific compared to general cell ablation approaches that have been used earlier on. In this review, we will give a detailed summary on different glial ablation studies, focusing on the adult mouse central nervous system and the functional readouts. We will also provide an outlook on how these approaches could be further exploited in the future. PMID: 28243193 [PubMed - in process] http://dlvr.it/NWDq7W

[neurogenpapers]

Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network.

PubMed: Related Articles Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network. Front Aging Neurosci. 2017;9:23 Authors: Martín-Jiménez CA, Salazar-Barreto D, Barreto GE, González J Abstract Astrocytes are the most abundant cells of the central nervous system; they have a predominant role in maintaining brain metabolism. In this sense, abnormal metabolic states have been found in different neuropathological diseases. Determination of metabolic states of astrocytes is difficult to model using current experimental approaches given the high number of reactions and metabolites present. Thus, genome-scale metabolic networks derived from transcriptomic data can be used as a framework to elucidate how astrocytes modulate human brain metabolic states during normal conditions and in neurodegenerative diseases. We performed a Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network with the purpose of elucidating a significant portion of the metabolic map of the astrocyte. This is the first global high-quality, manually curated metabolic reconstruction network of a human astrocyte. It includes 5,007 metabolites and 5,659 reactions distributed among 8 cell compartments, (extracellular, cytoplasm, mitochondria, endoplasmic reticle, Golgi apparatus, lysosome, peroxisome and nucleus). Using the reconstructed network, the metabolic capabilities of human astrocytes were calculated and compared both in normal and ischemic conditions. We identified reactions activated in these two states, which can be useful for understanding the astrocytic pathways that are affected during brain disease. Additionally, we also showed that the obtained flux distributions in the model, are in accordance with literature-based findings. Up to date, this is the most complete representation of the human astrocyte in terms of inclusion of genes, proteins, reactions and metabolic pathways, being a useful guide for in-silico analysis of several metabolic behaviors of the astrocyte during normal and pathologic states. PMID: 28243200 [PubMed - in process] http://dlvr.it/NWD6KG

[neurogenpapers]

Mutation Analysis of HTRA2 Gene in Chinese Familial Essential Tremor and Familial Parkinson's Disease.

PubMed: Related Articles Mutation Analysis of HTRA2 Gene in Chinese Familial Essential Tremor and Familial Parkinson's Disease. Parkinsons Dis. 2017;2017:3217474 Authors: He YC, Huang P, Li QQ, Sun Q, Li DH, Wang T, Shen JY, Du JJ, Cui SS, Gao C, Fu R, Chen SD Abstract Background. HTRA2 has already been nominated as PARK13 which may cause Parkinson's disease, though there are still discrepancies among these results. Recently, Gulsuner et al.'s study found that HTRA2 p.G399S is responsible for hereditary essential tremor and homozygotes of this allele develop Parkinson's disease by examining a six-generation family segregating essential tremor and essential tremor coexisting with Parkinson's disease. We performed this study to validate the condition of HTRA2 gene in Chinese familial essential tremor and familial Parkinson's disease patients, especially essential tremor. Methods. We directly sequenced all eight exons, exon-intron boundaries, and part of the introns in 101 familial essential tremor patients, 105 familial Parkinson's disease patients, and 100 healthy controls. Results. No exonic variant was identified, while one exon-intron boundary variant (rs2241028) and one intron variant (rs2241027) were detected, both with no clinical significance and uncertain function. There was no difference in allele, genotype, and haplotype between groups. Conclusions. HTRA2 exonic variant might be rare among Chinese Parkinson's disease and essential tremor patients with family history, and HTRA2 may not be the cause of familial Parkinson's disease and essential tremor in China. PMID: 28243480 [PubMed - in process] http://dlvr.it/NWCNb2

[neurogenpapers]

Bax-inhibitor-1 knockdown phenotypes are suppressed by Buffy and exacerbate degeneration in a Drosophila model of Parkinson disease.

PubMed: Related Articles Bax-inhibitor-1 knockdown phenotypes are suppressed by Buffy and exacerbate degeneration in a Drosophila model of Parkinson disease. PeerJ. 2017;5:e2974 Authors: M'Angale PG, Staveley BE Abstract BACKGROUND: Bax inhibitor-1 (BI-1) is an evolutionarily conserved cytoprotective transmembrane protein that acts as a suppressor of Bax-induced apoptosis by regulation of endoplasmic reticulum stress-induced cell death. We knocked down BI-1 in the sensitive dopa decarboxylase (Ddc) expressing neurons of Drosophila melanogaster to investigate its neuroprotective functions. We additionally sought to rescue the BI-1-induced phenotypes by co-expression with the pro-survival Buffy and determined the effect of BI-1 knockdown on the neurodegenerative α-synuclein-induced Parkinson disease (PD) model. METHODS: We used organismal assays to assess longevity of the flies to determine the effect of the altered expression of BI-1 in the Ddc-Gal4-expressing neurons by employing two RNAi transgenic fly lines. We measured the locomotor ability of these RNAi lines by computing the climbing indices of the climbing ability and compared them to a control line that expresses the lacZ transgene. Finally, we performed biometric analysis of the developing eye, where we counted the number of ommatidia and calculated the area of ommatidial disruption. RESULTS: The knockdown of BI-1 in these neurons was achieved under the direction of the Ddc-Gal4 transgene and resulted in shortened lifespan and precocious loss of locomotor ability. The co-expression of Buffy, the Drosophila anti-apoptotic Bcl-2 homologue, with BI-1-RNAi resulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human α-synuclein in Drosophila dopaminergic neurons results in neuronal degeneration, accompanied by the age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synuclein with BI-1-RNAi results in a slight decrease in lifespan coupled with an impairment in climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate subtle phenotypes that result from altered gene expression. The knockdown of BI-1 in the Drosophila developing eye under the direction of the GMR-Gal4 transgene results in reduced ommatidia number and increased disruption of the ommatidial array. Similarly, the co-expression of BI-1-RNAi with Buffy results in the suppression of the eye phenotypes. The expression of α-synuclein along with the knockdown of BI-1 resulted in reduction of ommatidia number and more disruption of the ommatidial array. CONCLUSION: Knockdown of BI-1 in the dopaminergic neurons of Drosophila results in a shortened lifespan and premature loss in climbing ability, phenotypes that appear to be strongly associated with models of PD in Drosophila, and which are suppressed upon overexpression of Buffy and worsened by co-expression with α-synuclein. This suggests that BI-1 is neuroprotective and its knockdown can be counteracted by the overexpression of the pro-survival Bcl-2 homologue. PMID: 28243526 [PubMed - in process] http://dlvr.it/NWBdBS

[neurogenpapers]

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

PubMed: Related Articles Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis. Acta Neuropathol. 2017 Feb 28;: Authors: Scekic-Zahirovic J, Oussini HE, Mersmann S, Drenner K, Wagner M, Sun Y, Allmeroth K, Dieterlé S, Sinniger J, Dirrig-Grosch S, René F, Dormann D, Haass C, Ludolph AC, Lagier-Tourenne C, Storkebaum E, Dupuis L Abstract Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. PMID: 28243725 [PubMed - as supplied by publisher] http://dlvr.it/NW9sry

[neurogenpapers]

Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants.

PubMed: Related Articles Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. Clin Genet. 2017 Feb 28;: Authors: Yoshimura A, Yuan JH, Hashiguchi A, Hiramatsu Y, Ando M, Higuchi Y, Nakamura T, Okamoto Y, Matsumura K, Hamano T, Sawaura N, Shimatani Y, Kumada S, Okumura Y, Miyahara J, Yamaguchi Y, Kitamura S, Haginoya K, Mitsui J, Ishiura H, Tsuji S, Takashima H Abstract Mutations in GDAP1 are responsible for heterogeneous clinical and electrophysiological phenotypes, with autosomal dominant or recessive inheritance pattern. From April 2007 to October 2014, using three state-of-art technologies, we conducted gene panel sequencing in a cohort of 1,030 patients with inherited peripheral neuropathies (IPNs), and 398 mutation-negative cases were further analyzed with whole-exome sequencing. We identified GDAP1 variants from 10 patients clinically diagnosed with Charcot-Marie-Tooth disease (CMT). The most frequent recessive variant in our cohort (5/10), c.740C>T (p.A247V), was verified to be associated with a founder event. We also detected three novel likely pathogenic variants: c.928C>T (p.R310W) and c.546delA (p.E183Kfs*23) in Case 2 and c.376G>A (p.E126K) in Case 8. Nerve conduction study or sural nerve biopsy of all 10 patients indicated axonal type peripheral neuropathy. We identified GDAP1 variants in approximately 1% of our cohort with IPNs, and established a founder mutation in half of these patients. Our study originally described the mutational spectrum and clinical features of GDAP1-related CMT patients in Japan. PMID: 28244113 [PubMed - as supplied by publisher] http://dlvr.it/NW92gh

[neurogenpapers]

miRNA-214 inhibits cellular proliferation and migration in glioma cells targeting caspase-1 involved in pyroptosis.

PubMed: miRNA-214 inhibits cellular proliferation and migration in glioma cells targeting caspase-1 involved in pyroptosis. Oncol Res. 2016 Dec 15;: Authors: Jiang Z, Yao L, Ma H, Xu P, Li Z, Guo M, Chen J, Bao H, Qiao S, Zhao Y, Shen J, Zhu M, Meyers C, Ma G, Xie C, Liu L, Wang H, Zhang W, Dong Q, Shen H, Lin Z Abstract Pyroptosis, is a type of pro-inflammatory programmed cell death mediated by caspase-1 activity and occurs in several types of eukaryotic tumor cells, including gliomas. MicroRNAs (miRNAs), small endogenous non-coding RNAs, have demonstrated as advantageous in glioma therapy. However, whether miRNAs regulate pyroptosis in glioma remains unknown. The current study found that caspase-1 expression was substantially increased in both glioma tissues as well as the glioma cell lines, U87 and T98G, while miR-214 expression was significantly downregulated. Luciferase reporter assay recognized caspase-1 as a target gene of miR-214. These findings deomonstrate that miR-214 could inhibit cell proliferation and migration through the regulation of pyroptosis intermediated by caspase-1 in glioma U87 and T98G cells and may suggest a novel therapeutic for intervention of glioma. PMID: 28244850 [PubMed - as supplied by publisher] http://dlvr.it/NW8HPJ

[neurogenpapers]

High BMI levels associate with reduced mRNA expression of IL10 and increased mRNA expression of iNOS (NOS2) in human frontal cortex.

PubMed: High BMI levels associate with reduced mRNA expression of IL10 and increased mRNA expression of iNOS (NOS2) in human frontal cortex. Transl Psychiatry. 2017 Feb 28;7(2):e1044 Authors: Lauridsen JK, Olesen RH, Vendelbo J, Hyde TM, Kleinman JE, Bibby BM, Brock B, Rungby J, Larsen A Abstract Several studies link increasing body mass index (BMI) to cognitive decline both as a consequence of obesity per se and as a sequela of obesity-induced type 2 diabetes. Obese individuals are prone to a chronic low-grade inflammation as the metabolically active visceral fat produces proinflammatory cytokines. Animal studies indicate that these cytokines can cross the blood-brain barrier. Such crossover could potentially affect the immune system in the brain by inducing gene expression of proinflammatory genes. The relationship between obesity and neuroinflammation in the human brain is currently unknown. Therefore we aim to examine the relationship between BMI and gene expression of central inflammatory markers in the human frontal cortex. Microarray data of 141 neurologically and psychiatrically healthy individuals were obtained through the BrainCloud database. A simple linear regression analysis was performed with BMI as variable on data on IL10, IL1β, IL6, PTGS2 (COX2) and NOS2 (iNOS). Increasing BMI is associated with a decrease in the mRNA expression of IL10 (P=0.014) and an increase in the expression of NOS2 (iNOS; P=0.040). Expressions of IL10 and NOS2 (iNOS) were negatively correlated (P http://dlvr.it/NW7Vyd