Retrovirus reactivation in CHMP2BIntron5 models of frontotemporal dementia

Fort-Aznar, Laura; Ugbode, Chris; Sweeney, Sean T.

doi:10.1093/hmg/ddaa142

Cited by 7 publications

(10 citation statements)

References 62 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…C9orf72 HRE carriers and a subset of sporadic FTD/ALS cases show evidence of LINE1 element de-repression and retrotransposition, events thought to be related to loss of nuclear TDP-43 (Liu et al, 2019) (Prudencio et al, 2017) (Tam et al, 2019). In addition, heightened TE expression occurs in the context of tauopathies (Guo et al, 2018; Sun et al, 2018) and a distinct FTD-related proteinopathy due to pathogenic CHMP2B variation (Skibinski et al, 2005; Mackenzie and Neumann, 2016) (Fort-Aznar et al, 2020). Collectively, these findings suggest that TE de-repression may represent a general phenomenon occurring in multiple forms of neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, transposable element (TE) activation may occur in the context of other proteinopathies as well—tau neuropathology also appears to induce TE expression (Guo et al, 2018; Sun et al, 2018). Remarkably, a Drosophila model of pathogenic CHMP2B variation, which causes FTD characterized by atypical TDP-43- and tau-negative neuropathology (Skibinski et al, 2005; Mackenzie and Neumann, 2016), also involves augmented TE expression (Fort-Aznar et al, 2020), suggesting that heightened TE expression and retrotransposition may represent a general mechanism underlying multiple forms of neurodegeneration. However, to our knowledge, it is unknown whether this activation occurs in the periphery outside of the brain.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Radiogenomics of C9orf72 expansion carriers reveals global transposable element de-repression and enables prediction of thalamic atrophy and clinical impairment

Bonham

Geier

Sirkis

et al. 2022

Preprint

View full text Add to dashboard Cite

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread de-repression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used the FreeSurfer pipeline and its extensions to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78) on atrophy of thalamic nuclei. We also generated a novel, whole-blood RNA-seq dataset to determine the relationships between peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element, L1HS. L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from HRE carriers revealed atrophy of specific thalamic nuclei; demonstrated that C9orf72 levels relate to clinical severity; and identified marked de-repression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Radiogenomics of C9orf72 expansion carriers reveals global transposable element de-repression and enables prediction of thalamic atrophy and clinical impairment

Bonham

Geier

Sirkis

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This process permits to map cells in vivo with new integration events of gypsy transposons in a given tissue and developmental stage ( Table 1 ). For examples, the gypsy -TRAP line provides evidence to support ideas that gypsy are activated in an aged fly brain ( 84 ); in aged fat body (equivalent to liver in mammal) ( 86 , 87 ); in aged fly intestine ( 88 ); in fly model of tauopathy ( 89 ); in FTD–ALS causing CHMP2B Intron5 mutation ( 90 ); in the developing mesodermal tissue with histone 3 lysine 9 (H3K9) substituted by arginine (H3R9) ( 91 ).…”

Section: Visualizing Mobilization Of Tes With Cellular Resolutionmentioning

confidence: 93%

Ongoing endeavors to detect mobilization of transposable elements

Lee

Moon

2022

BMB Rep

View full text Add to dashboard Cite

Transposable elements (TEs) are DNA sequences capable of mobilization from one location to another in the genome. Since the discovery of ‘ Dissociation ( Dc ) locus’ by Barbara McClintock in maize (1), mounting evidence in the era of genomics indicates that a significant fraction of most eukaryotic genomes is composed of TE sequences, involving in various aspects of biological processes such as development, physiology, diseases and evolution. Although technical advances in genomics have discovered numerous functional impacts of TE across species, our understanding of TEs is still ongoing process due to challenges resulted from complexity and abundance of TEs in the genome. In this mini-review, we briefly summarize biology of TEs and their impacts on the host genome, emphasizing importance of understanding TE landscape in the genome. Then, we introduce recent endeavors especially in vivo retrotransposition assays and long read sequencing technology for identifying de novo insertions/TE polymorphism, which will broaden our knowledge of extraordinary relationship between genomic cohabitants and their host.

show abstract

“…It was found than neuronal expression of CHMP2BIntron5 causes an increased activity of the endogenous drosophila RV, called gypsy, in the nervous system. Genetically blocking Drosophila gypsy activation or pharmacologically inhibiting viral reverse transcriptase activity stopped degenerative phenotypes observed in fly and rat neurons [ 65 ].…”

Section: Herv Dysregulation Ad and Neurological Diseasesmentioning

confidence: 99%

“…Since FTD appears to overlap genetically and pathologically with amyotrophic lateral sclerosis (ALS), the authors [ 65 ] claimed that their observations may also further contribute to previous discoveries of HERV activation in ALS affected patients.…”

Section: Herv Dysregulation Ad and Neurological Diseasesmentioning

confidence: 99%

Activation of Endogenous Retrovirus, Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer’s Disease

Licastro

Porcellini

2021

IJMS

View full text Add to dashboard Cite

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer’s disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.

show abstract

Retrovirus reactivation in CHMP2BIntron5 models of frontotemporal dementia

Cited by 7 publications

References 62 publications

Radiogenomics of C9orf72 expansion carriers reveals global transposable element de-repression and enables prediction of thalamic atrophy and clinical impairment

Radiogenomics of C9orf72 expansion carriers reveals global transposable element de-repression and enables prediction of thalamic atrophy and clinical impairment

Ongoing endeavors to detect mobilization of transposable elements

Activation of Endogenous Retrovirus, Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer’s Disease

Contact Info

Product

Resources

About