Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10-5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS

Pitx3-Cre driven expression of eYfp marks transient expression of Pitx3 in a medial non-dopaminergic cell-group.

<p>A) In depth analysis through Th and eYfp co-localization of non-dopaminergic regions that express eYfp. B) Enlarged figures of boxes marked in A. C) Co-localistion of Yfp with 5-Ht staining at 4 separate A/P positions from left to right (top 4 panels). Higher magnification of the boxed areas are presented in the lower 2 panels, clearly showing that the Yfp positive neurons do not co-localise with 5-HT neurons. IF: interfascicular nucleus; IPF: interpeduncular fossa; RLi: rostral linear nucleus of the raphe; CLi:caudal linear nucleus of the raphe.</p

Pitx3-Cre driven eYfp expression starts between E12.5 and E13.5 and marks the ventral tegmentum, overlapping with Th.

<p>A) Th and eYfp co-localization in sagittal sections of the ventral mesodiencephalic region. Note that at this stage eYfp is not detected. B) Th and eYfp seperate as well as co-localization in sagittal sections of the ventral mesodiencephalic region. At this stage co-localization can be found but also some areas where Th and eYfp are uncoupled. C) Similar analysis as in B, on E14.5 material, confirming the Yfp and Th distribution. The white arrows indicates a medial/rostral region where Yfp is expressed in cells that do not express Th. L: lateral; M: medial.</p

Pitx3-Cre driven expression of eYfp co-localizes with all Th positive neurons.

<p>A) Th and eYfp expression in the control LoxP-stop-LoxP-eYfp animal. Note that only Th is expressed in these animals. B) Co-localization of Th and eYfp in the mdDA neuronal region. Note the complete overlap of Th positive neurons with eYfp. C) Enlarged figures of boxes as marked in B. White arrows: indication of the regions and cells where there is eYfp expression with no Th co-localization.</p

Pitx3-Cre driven eYfp expression outside the brain maps to the muscle.

<p>A) Representation of the eYfp muscle expression in the developing embryo at 2 stages of development. B) Enlarged figures of boxes marked in A. C) Schematic representation of the recombinant knock-in construct indicating the position and the 3′-restricted flank of the alternative exon1 position. Figure details as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042641#pone-0042641-g001" target="_blank">figure 1</a>.</p

Fc gamma receptor IIIA genotype is associated with rituximab response in antimyelin-associated glycoprotein neuropathy

Background Treatment with anti-B cell antibody rituximab may ameliorate the disease course in a subgroup of patients with polyneuropathy associated with IgM monoclonal gammopathy. Polymorphisms of leukocyte IgG receptors (Fc gamma R) that influence efficiency of antibody-dependent cell-mediated cytotoxicity determine rituximab efficacy in patients with lymphoma and autoimmune disease. Objective To investigate the association of Fc gamma RIIA and Fc gamma RIIIA polymorphisms with the response to rituximab treatment in a cohort of patients with polyneuropathy associated with IgM monoclonal gammopathy (PNP-IgM) with and without antimyelin-associated glycoprotein antibodies. Methods We determined Fc gamma RIIA-R/H131 and Fc gamma RIIIA-V/F158 genotypes in 27 patients with PNP-IgM using allele-specific PCR and Sanger sequencing. Results The Fc gamma RIIIA-V/V158 genotype was associated with functional improvement (p=0.02) after 1 year. Conclusions Fc gamma RIIIA polymorphisms are potential biomarkers for response to rituximab treatment in polyneuropathy associated with IgM monoclonal gammopath

FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6+/- and FoxO6-/- mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6. We then show that FoxO6 binds to DAF-16-binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression. Finally, ectopic Plxna4 expression restores radial migration in FoxO6+/- and siRNA-mediated knockdown models. In conclusion, the presented data provide insights into the molecular mechanisms whereby transcriptional programs drive cortical development

C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits

Objective: How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain- and loss-of-function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss-of-function in mice. Methods: We generated and analyzed a conditional C9orf72 knockout mouse model. C9orf72fl/fl mice were crossed with Nestin-Cre mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP-43 mislocalization. In addition, motor function and survival were assessed. Results: Neural-specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival. Interpretation: Our data suggest that C9orf72 loss-of-function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72-associated ALS

The role of de novo mutations in the development of amyotrophic lateral sclerosis

The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 x 10(-15)). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk