Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Tam, Oliver H.; Rozhkov, Nikolay V.; Shaw, Regina; Kim, Duyang; Hubbard, Isabel; Fennessey, Samantha; Propp, Nadia; Fagegaltier, Delphine; Harris, Brent T.; Ostrow, Lyle W.; Phatnani, Hemali; Ravits, John; Dubnau, Josh; Hammell, Molly

doi:10.1016/j.celrep.2019.09.066

Cited by 202 publications

(172 citation statements)

References 63 publications

(114 reference 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%

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis

Saul

Hutchins

Reiman

et al. 2020

acta neuropathol commun

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The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development.

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Section: Discussionsupporting

confidence: 68%

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis

Saul

Hutchins

Reiman

et al. 2020

acta neuropathol commun

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“…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%

Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS

et al. 2020

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Expansion of a (G 4 C 2) n repeat in C9orf72 causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the link of the five repeat-encoded dipeptide repeat (DPR) proteins to neuroinflammation, TDP-43 pathology, and neurodegeneration is unclear. Poly-PR is most toxic in vitro, but poly-GA is far more abundant in patients. To directly compare these in vivo, we created congenic poly-GA and poly-PR mice. 40% of poly-PR mice were affected with ataxia and seizures, requiring euthanasia by 6 weeks of age. The remaining poly-PR mice were asymptomatic at 14 months of age, likely due to an 80% reduction of the transgene mRNA in this subgroup. In contrast, all poly-GA mice showed selective neuron loss, inflammation, as well as muscle denervation and wasting requiring euthanasia before 7 weeks of age. In-depth analysis of peripheral organs and blood samples suggests that peripheral organ failure does not drive these phenotypes. Although transgene mRNA levels were similar between poly-GA and affected poly-PR mice, poly-GA aggregated far more abundantly than poly-PR in the CNS and was also found in skeletal muscle. In addition, TDP-43 and other disease-linked RNA-binding proteins co-aggregated in rare nuclear inclusions in the hippocampus and frontal cortex only in poly-GA mice. Transcriptome analysis revealed activation of an interferon-responsive pro-inflammatory microglial signature in end-stage poly-GA but not poly-PR mice. This signature was also found in all ALS patients and enriched in C9orf72 cases. In summary, our rigorous comparison of poly-GA and poly-PR toxicity in vivo indicates that poly-GA, but not poly-PR at the same mRNA expression level, promotes interferon responses in C9orf72 disease and contributes to TDP-43 abnormalities and neuron loss selectively in disease-relevant regions.

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“…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%

An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

Pfaff

Bubb

Quinn

et al. 2020

IJMS

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Long interspersed element-1 (LINE-1/L1s) contributes 17% of the human genome with more than 1 million elements present; however, fewer than 100 of these have evidence for being retrotransposition competent (RC). In addition to those RC-L1s present in the reference genome, there are a small number of known non-reference L1 insertions that are also retrotransposition competent. L1 activity, whether through the potentially detrimental effects of their mRNA or protein expression or somatic retrotransposition events, has been linked to several neurological conditions. The polymorphic nature of both reference and non-reference RC-L1s in terms of their presence or absence will result in individuals harboring a different combination of these elements and it is currently unknown if this type of germline variation contributes to the risk of neurological disease. Here, we utilized whole-genome sequencing data from 178 healthy controls and 372 Parkinson’s disease (PD) subjects from the Parkinson’s Progression Markers Initiative (PPMI) to investigate the role of RC-L1s in PD. In the PPMI cohort, we identified 22 reference and 50 non-reference polymorphic RC-L1 loci. Focusing on 16 highly active RC-L1 loci, an increased burden of these elements (≥9) was associated with PD (OR 1.25, 95% CI 1.03–1.51, p = 0.02). In addition, we identified significant associations of progression markers of PD and the burden of highly active RC-L1s. This study has identified a novel type of genetic element associated with PD risk and disease progression.

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Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Cited by 202 publications

References 63 publications

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis

Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS

An Increased Burden of Highly Active Retrotransposition Competent L1s Is Associated with Parkinson’s Disease Risk and Progression in the PPMI Cohort

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