Angiogenin Levels and ANG Genotypes: Dysregulation in Amyotrophic Lateral Sclerosis

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Abstract

Objective

To determine whether 5 single nucleotide polymorphisms (SNPs) associate with ALS in 3 different populations. We also assessed the contribution of genotype to angiogenin levels in plasma and CSF.

Methods

Allelic association statistics were calculated for polymorphisms in the ANG gene in 859 patients and 1047 controls from Sweden, Ireland and Poland. Plasma, serum and CSF angiogenin levels were quantified and stratified according to genotypes across the ANG gene. The contribution of SNP genotypes to variance in circulating angiogenin levels was estimated in patients and controls.

Results

All SNPs showed association with ALS in the Irish group. The SNP rs17114699 replicated in the Swedish cohort. No SNP associated in the Polish cohort. Age- and sex-corrected circulating angiogenin levels were significantly lower in patients than in controls (p<0.001). An allele dose-dependent regulation of angiogenin levels was observed in controls. This regulation was attenuated in the ALS cohort. A significant positive correlation between CSF plasma angiogenin levels was present in controls and abolished in ALS.

Conclusions

ANG variants associate with ALS in the Irish and Swedish populations, but not in the Polish. There is evidence of dysregulation of angiogenin expression in plasma and CSF in sporadic ALS. Angiogenin expression is likely to be important in the pathogenesis of ALS.

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Most cited references 12

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A genome-wide association study of sporadic ALS in a homogenous Irish population.

Simon Cronin, Stephen Berger, Jinhui Ding … (2008)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive limb or bulbar weakness. Efforts to elucidate the disease-associated loci have to date produced conflicting results. One strategy to improve power in genome-wide studies is to genotype a genetically homogenous population. Such a population exhibits extended linkage disequilibrium (LD) and lower allelic heterogeneity to facilitate disease gene mapping. We sought to identify associated variants for ALS in the Irish, a stable population of relatively homogenous genetic background, and to replicate these findings in larger genetically out-bred populations. We conducted a genome-wide association study in 432 Irish individuals using Illumina HumanHap 550K single nucleotide polymorphism chips. We demonstrated extended LD and increased homogeneity in the Irish sample when compared to an out-bred population of mixed European ancestry. The Irish scan identified 35 loci associated with P-values below 0.0001. For replication, we identified seven chromosomal regions commonly associated in a joint analysis of genome-wide data on 958 ALS cases and 932 controls from Ireland and the previously published datasets from the US and The Netherlands. When pooled, the strongest association was a variant in the gene encoding DPP6, a component of type A neuronal transmembrane potassium channels. Further confirmation of the candidate loci is warranted in additional genome-wide datasets. We have made our individual genotyping data publicly available, contributing to a powerful world-wide resource to refine our understanding of the genetics of sporadic ALS.

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New roles for VEGF in nervous tissue--beyond blood vessels.

Jeffrey M Rosenstein, David Krum (2004)

Vascular endothelial growth factor (VEGF) is a secreted dimeric polypeptide that until recently has been believed to be a specific mitogen for endothelial cells subserving angiogenesis and permeability in development and after injury. Recent studies have depicted the localization of VEGF and its receptors on neurons and astrocytes and it has been shown to induce neuritic growth and to provide neuroprotection particularly after ischemia or spinal cord injuries. VEGF also shares common receptor signaling with the guidance molecule SEMA3A and thus could have an additional role linking the coordinated patterning of developing vascular and nervous tissue. It is now apparent that VEGF's role in nervous tissue is pleiotropic in nature, and further elucidation of its mechanisms of action may serve as a key substrate in understanding aspects of neural repair and development.

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Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons.

Vasanta Subramanian, Kshitish K. Acharya, Mary Crabtree (2008)

Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disorder affecting upper and lower motor neurons (MNs). The molecular mechanisms underlying ALS are poorly understood. Mutations in SOD1 is one of the known causes of ALS but occur only in a very small number of cases of ALS. Interestingly, mutations in human angiogenin (hANG), a member of the ribonuclease A (RNase A) superfamily known to be involved in neovascularization, have been recently reported in patients with ALS, but the effects of these mutations on MN differentiation and survival has not been investigated. We have used the well-characterized pluripotent P19 embryonal carcinoma (EC) cell culture model of neuro-ectodermal differentiation to study the effects of hANG-ALS variants on MN differentiation and survival. Here we report that P19 EC cells induced to differentiate in the presence of hANG and hANG-ALS-associated variants internalize the wild-type and variant proteins. The P19 EC cells differentiate to form neurons but the ability of the neurites to extend and make contacts with neighbouring neurites is compromised when treated with the hANG-ALS variants. In addition, hANG-ALS variants also have a cytotoxic effect on MNs leading to their degeneration. hANG was able to protect neurons from hypoxia-induced cell death, but the variants of hANG implicated in ALS lacked the neuroprotective activity. Our findings show that ANG plays an important role in neurite extension/pathfinding and survival providing a causal link between mutations in hANG and ALS.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2010

Publication date (Electronic): 10 November 2010

Volume: 5

Issue: 11

Electronic Location Identifier: e15402

Affiliations

[1 ]Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland

[2 ]Department of Neurology, Beaumont Hospital, Dublin, Ireland

[3 ]Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

[4 ]Human Science Research Unit, Faculty of Education and Health Sciences, University of Limerick, Limerick, Ireland

[5 ]Royal College of Surgeons Ireland, Dublin, Ireland

[6 ]Statistical Consulting Unit, University of Limerick, Limerick, Ireland

[7 ]Department of Neurology, Jagiellonian University, Krakow, Poland

[8 ]Department of Pharmacology and Clinical Neurosciences, Umeå University Hospital, Umeå, Sweden

Aarhus University, Denmark

Author notes

* E-mail: mclaugr@ 123456tcd.ie

Conceived and designed the experiments: OH SC MG. Performed the experiments: JP SC RLM. Analyzed the data: RLM OH WM DSL PJ JS. Contributed reagents/materials/analysis tools: PMA BT AS DB PJ OH. Wrote the paper: RLM JP DSL SC OH.

Article

Publisher ID: PONE-D-10-00373

DOI: 10.1371/journal.pone.0015402

PMC ID: 2978104

PubMed ID: 21085671

SO-VID: 49df2283-3e46-4480-a07b-a2a459a2ae46

Copyright © McLaughlin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 3 August 2010

Date accepted : 10 September 2010

Page count

Pages: 6

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