A HML6 endogenous retrovirus on chromosome 3 is upregulated in amyotrophic lateral sclerosis motor cortex

Jones, Ashley; Iacoangeli, Alfredo; Adey, Brett N.; Bowles, Harry; Shatunov, Aleksey; Troakes, Claire; Garson, Jeremy A.; McCormick, Adele L.; Al‐Chalabi, Ammar

doi:10.1038/s41598-021-93742-3

Cited by 15 publications

(20 citation statements)

References 73 publications

(77 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Moreover, HERV-Ks—which, like the murine ERV2s, are members of the betaretrovirus-like supergroup of LTR retrotransposons—have been linked to amyotrophic lateral sclerosis (ALS) or motor neuron disease 51 – 53 (but see also Garson et al 54 ), including some cases infected with the Human Immunodeficiency Virus (HIV), an exogeneous LTR retrovirus 55 . In addition, the genetic risk architecture of ALS shows a modest association with genomic loci harboring HERV insertions 53 . Interestingly, we observed that genomic loci harboring HERV-Ks are significantly enriched in trans chromosomal Hi-C contacts in human neurons ( p = 1.42 × 10 −16 , Fisher’s 2 × 2 exact testing), an effect driven primarily by sequences with strong synteny with murine B 2 megadomains (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

et al. 2021

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Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B2NeuN+ megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B2NeuN+ contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B2NeuN+ disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

et al. 2021

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“…Several studies have found evidence of reverse transcriptase activity in brain, cerebrospinal fluid (CSF), and blood of patients with ALS (reviewed in Alfahad and Nath 16 ), which was identified to be encoded by the pol gene of HML-2 in brains of patients with sporadic ALS. 17 Although two groups did not see a difference between HERV-K gene expression between ALS and controls, [18][19][20] we have identified activation of specific loci in ALS brain with ORFs for HML-2 envelope (Env). 17,21 Additionally, HML-2 Env expression was detected in cortical and anterior horn cells of the spinal cord of ALS patients, and a transgenic mouse model expressing the HML-2 Env protein recapitulated many of the phenotypic and pathological features seen in ALS.…”

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confidence: 77%

Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic

Steiner

Bachani

Malik

et al. 2022

Annals of Neurology

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Objective: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and in transgenic mice results in neurotoxicity and neurodegeneration, and mice expressing HML-2 Env display behavioral and neuromuscular characteristics resembling ALS. This study aims to characterize the neurotoxic properties of HML-2 Env. Methods: Env neurotoxicity was detected in ALS cerebrospinal fluid and confirmed using recombinant Env protein in a cell-based assay and a mouse model. The mechanism of neurotoxicity was assessed with immunoprecipitation followed by mass spectrometry and Western blot, and by screening a panel of inhibitors. Results: We observed that recombinant HML-2 Env protein caused neurotoxicity resulting in neuronal cell death, retraction of neurites, and decreased neuronal electrical activity. Injection of the Env protein into the brains of mice also resulted in neuronal cell death. HML-2 Env protein was also found in the cerebrospinal fluid of patients with sporadic ALS. The neurotoxic properties of the Env and the cerebrospinal fluid could be rescued with the anti-Env antibody. The Env was found to bind to CD98HC complexed to β1 integrin on the neuronal cell surface. Using a panel of compounds to screen for their ability to block Env-induced neurotoxicity, we found that several compounds were protective and are linked to the β1 integrin pathway. Interpretation: HERV-K Env is released extracellularly in ALS and causes neurotoxicity via a novel mechanism. Present results pave the way for new treatment strategies in sporadic ALS.

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“…The predominant focus in ALS has been characterising loci specific HERV expression with differences observed in whether there is a significant upregulation or not of HERV loci [ 6 , 7 , 9 ]. One recent study profiling the loci specific expression of HERVs identified one HERV locus (HML6_3p21.31c) that was consistently upregulated in the motor cortex and cerebellum of individuals with ALS compared to controls [ 31 ]. Therefore, we sought to address the question of L1 loci specific expression in ALS utilising RNA-sequencing data from multiple tissues obtained from the New York Genome Center Target ALS cohort.…”

Section: Discussionmentioning

confidence: 99%

Locus specific reduction of L1 expression in the cortices of individuals with amyotrophic lateral sclerosis

et al. 2022

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The activation and dysregulation of retrotransposons has been identified in the CNS of individuals with the fatal neurodegenerative disorder Amyotrophic lateral sclerosis (ALS). This includes elements from multiple different families and subfamilies of retrotransposons, however there is limited knowledge of the specific loci from which this expression occurs in ALS. The long interspersed element-1 (L1) is the only autonomous retrotransposon in the human genome and members of this family of elements maintain the ability to mobilise. Despite L1s contributing to 17% of the human genome only 80–100 L1s encode the required proteins for mobilisation and are retrotransposition competent. Identifying the specific loci from which L1 expression occurs will inform on the potential functional consequences of their expression, such as the potential for somatic retrotransposition or DNA damage caused by the endonuclease activity of the ORF2 protein of the L1. Here we characterised L1 loci expression using the L1EM tool (https://github.com/FenyoLab/L1EM) in RNA sequencing data from 518 samples across four tissues (motor cortex, frontal cortex, cerebellum and cervical spinal cord) in the Target ALS cohort obtained from the New York Genome Center. There was a significant reduction in total intact L1 expression (those that encode functional proteins) in two brain regions of individuals with ALS compared to controls and clustering of the ALS brain regions occurred based on their intact L1 expression profile. Although overall the levels of L1 expression were reduced in ALS/ALS with other neurological disorder (ND) there were individuals in which L1s were expressed at much higher levels than the rest of the ALS/ALSND cohort. Expressed L1 loci were more frequently located in introns compared to those not expressed and the level of L1 expression positively correlated with the expression of the gene in which it was located. Significant differences were observed in the expression profiles of L1s in ALS and specific features of these elements, such as location in the genome and whether or not they are intact, were significantly associated with those that were expressed in the cohort.

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A HML6 endogenous retrovirus on chromosome 3 is upregulated in amyotrophic lateral sclerosis motor cortex

Cited by 15 publications

References 73 publications

Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions

Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic

Locus specific reduction of L1 expression in the cortices of individuals with amyotrophic lateral sclerosis

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