2019
DOI: 10.1016/j.celrep.2019.09.066
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Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Abstract: SUMMARY Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecul… Show more

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Cited by 220 publications
(236 citation statements)
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“…S5) characterized by elevated levels of multiple cytokines and immunokines, suggesting the existence of a subtype of ALS patients with increased inflammation. This phenotype is highly reminiscent of recent findings in postmortem ALS cortex that described distinct molecular subtypes of ALS, with 19% of assayed cortex samples showing signatures of activated glia and immune cells [71].…”
Section: Discussionsupporting
confidence: 68%
“…S5) characterized by elevated levels of multiple cytokines and immunokines, suggesting the existence of a subtype of ALS patients with increased inflammation. This phenotype is highly reminiscent of recent findings in postmortem ALS cortex that described distinct molecular subtypes of ALS, with 19% of assayed cortex samples showing signatures of activated glia and immune cells [71].…”
Section: Discussionsupporting
confidence: 68%
“…Interestingly, IFNα levels are higher in the CSF of C9orf72 ALS compared to sporadic ALS [51]. Transcriptome analysis in cortex samples from ALS cases identified a subgroup of patients with high microglia/interferon response, without enrichment in C9orf72 cases, but the spinal cord was not analyzed in that study [60]. Comparing gene expression of isolated GA-Nes microglia to recently published microglia expression signatures from single cell RNAseq experiments [19,26,40,56] highlights the role of pro-inflammatory microglia subpopulations characterized by a strong interferon response.…”
Section: Tdp-43 and Other Disease-linked Rna-binding Proteins Form Numentioning
confidence: 89%
“…Cellular assays have demonstrated the ability of L1s to retrotranspose in neural progenitor cells and in mature nondividing neurons [11,12]. Differential expression of retrotransposon mRNA and proteins, including those of L1s, has also been identified in several different neurological conditions, including Rett syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, ataxia telangiectasia, and Aicardi-Goutieres syndrome [11,[13][14][15][16][17][18]. L1s have also been shown to be activated in cellular and mouse models of Parkinson's disease (PD) [19,20].…”
Section: Introductionmentioning
confidence: 99%