Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

Jones, Ashley; Troakes, Claire; King, Andrew; Sahni, Vibhu; Jong, Simone de; Bossers, Koen; Papouli, Efterpi; Mirza, Muddassar M.; Al‐Sarraj, Safa; Shaw, Pamela J.; Kirby, Janine; Veldink, Jan H.; Macklis, Jeffrey D.; Powell, John; Al‐Chalabi, Ammar

doi:10.1016/j.neurobiolaging.2015.02.017

Cited by 20 publications

(18 citation statements)

References 43 publications

(36 reference statements)

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“…It is a common dilemma for gene expression studies the inference of causality: transcriptomic changes may be a consequence of ALS, rather than its cause53. Nonetheless, many of the pathways highlighted by our experiments turned out to be involved in ALS, supporting potential pathogenetic causality.…”

Section: Discussionmentioning

confidence: 58%

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Riva

Clarelli

Domi

et al. 2016

Sci Rep

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The aim of the present study is to investigate the molecular pathways underlying amyotrophic lateral sclerosis (ALS) pathogenesis within the peripheral nervous system. We analyzed gene expression changes in human motor nerve diagnostic biopsies obtained from eight ALS patients and seven patients affected by motor neuropathy as controls. An integrated transcriptomics and system biology approach was employed. We identified alterations in the expression of 815 genes, with 529 up-regulated and 286 down-regulated in ALS patients. Up-regulated genes clustered around biological process involving RNA processing and protein metabolisms. We observed a significant enrichment of up-regulated small nucleolar RNA transcripts (p = 2.68*10-11) and genes related to endoplasmic reticulum unfolded protein response and chaperone activity. We found a significant down-regulation in ALS of genes related to the glutamate metabolism. Interestingly, a network analysis highlighted HDAC2, belonging to the histone deacetylase family, as the most interacting node. While so far gene expression studies in human ALS have been performed in postmortem tissues, here specimens were obtained from biopsy at an early phase of the disease, making these results new in the field of ALS research and therefore appealing for gene discovery studies.

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Section: Discussionmentioning

confidence: 58%

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Riva

Clarelli

Domi

et al. 2016

Sci Rep

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“…High level of apoB might also lead to neuronal loss through the downregulation of vascular endothelial growth factor (VEGF) receptor 1 . VEGF has been associated with motor neuron degeneration in individuals with ALS, possibly through affecting both neurons and glia . The finding on apoB might also partially explain the reported inverse association of n‐3 polyunsaturated fatty acids, which are known to modulate LDL‐C, with ALS risk .…”

Section: Discussionmentioning

confidence: 99%

Blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: A more than 20‐year follow‐up of the Swedish AMORIS cohort

Mariosa

Hammar

Malmström

et al. 2017

Annals of Neurology

117

112

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“…Various epigenetic mechanisms, including DNA methylation [such as hypermethylation of CpG islands in C9ORF72 expansion (24)], histone remodeling, abnormal miRNA biogenesis, and other silencing mechanisms have been described in sALS (25). In the CNS, changes in the expression of C9ORF72 , MATR , and VEGFA are present in affected regions (26). Transcriptional alterations in peripheral blood mononuclear cells (PBMCs) involve the genes B2M, ACTG1, DYNLT1, SKIV2L2, C12orf35, TARDBP , and ILKAP (27).…”

mentioning

confidence: 99%

Epigenetic changes in T‐cell and monocyte signatures and production of neurotoxic cytokines in ALS patients

et al. 2016

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We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, the ALS twin developed higher abundances of the CD14 macrophages and lower abundances of T cells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in the methylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin's PBMCs spontaneously produced IL-6 and TNF-α, whereas PBMCs of the healthy twin produced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence of memory T cells in both twins, but effector T cells only in the ALS twin. The ALS twin's PBMC supernatants, but not the healthy twin's, were toxic to rat cortical neurons, and this toxicity was strongly inhibited by an IL-6 receptor antibody (tocilizumab) and less well by TNF-α and IL-1β antibodies. The putative neurotoxicity of IL-6 and TNF-α is in agreement with a high expression of these cytokines on infiltrating macrophages in the ALS spinal cord. We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in the phenotype and treatment of certain individuals with ALS.-Lam, L., Chin, L., Halder, R. C., Sagong, B., Famenini, S., Sayre, J., Montoya, D., Rubbi L., Pellegrini, M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients.

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Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

Cited by 20 publications

References 43 publications

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis

Blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: A more than 20‐year follow‐up of the Swedish AMORIS cohort

Epigenetic changes in T‐cell and monocyte signatures and production of neurotoxic cytokines in ALS patients

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