Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients

Abstract

Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls. Transcripts from multiple classes and subclasses of repetitive elements (LINEs, endogenous retroviruses, DNA transposons, simple repeats, etc.) were significantly increased in the frontal cortex of C9orf72 ALS patients. A large collection of patient samples, representing both C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts. These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases. While previous studies suggest an important link between TDP-43 and repetitive element biology, our data indicate that TDP-43 pathology alone is insufficient to account for the observed changes in repetitive elements in ALS/FTLD. Instead, we found that repetitive element expression positively correlated with RNA polymerase II activity in postmortem brain, and pharmacologic modulation of RNA polymerase II activity altered repetitive element expression in vitro. We conclude that increased RNA polymerase II activity in ALS/FTLD may lead to increased repetitive element transcript expression, a novel pathological feature of ALS/FTLD.

Transposable Element Exprssion in Tumors is Associated with Immune Infiltration and Increased Antigenicity

“…Human DNA transposons had been thought to be completely inactive, based on the lack of evidence for transposition in the human genome (23). Although these data cannot address transposition, our results, coupled with other recent studies (24,25), suggest active gene expression by DNA transposons.…”

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

“…While previous studies have linked TDP-43 to transposon binding in human cells and to transposon regulation in animal models (Krug et al, 2017;Wenxue Li et al, 2015), this is the first to link TDP-43 bound transposon transcripts to those that are de-silenced in human cells and to demonstrate that these same targets are de-silenced in a subset of human ALS patients. Additional mechanisms for transposon de-silencing in ALS patients with C9orf72 repeat expansions have been suggested Prudencio et al, 2017;Y.-J. Zhang et al, 2019), though we note that C9orf72 status was not associated with the ALS-TE group in this study.…”

“…A hexanucleotide repeat expansion in C9orf72 is the most common pathogenic alteration associated with the development of ALS, both familial and sporadic (Majounie et al, 2012). Moreover, previous studies have noticed a slight trend toward higher TE expression in patients carrying C9orf72 mutations Prudencio et al, 2017;Y.-J. Zhang et al, 2019) .…”

“…However, a role for TDP-43 in general retrotransposon silencing has not been demonstrated, nor whether TDP-43 pathology in ALS patients correlates with retrotransposon de-silencing. Of note, prior studies have identified a link between retrotransposon expression and repeat expansion in another ALS-linked gene, C9orf72 (Prudencio et al, 2017). Finally, contrasting studies either failed to find an enrichment for elevated levels of the endogenous retrovirus HERV-K in a smaller sample of ALS tissues or suggested that TDP-43 may activate HERV-K transcription rather than silencing this particular retrotransposon (Wenxue Li et al, 2015).…”

Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice

“…RNA dysregulation is thought to play a role in C9orf72 ALS/FTD (Butti & Patten, 2018, Prudencio, Gonzales et al, 2017 but little is known about how the transcriptome is affected early in the course of disease or how these changes progress over time. To look for transcriptomic abnormalities that occur during disease progression, we performed RNA sequencing on frontal cortex samples from ten female C9-500 mice at 20 weeks of age with no overt cage behavior abnormalities (C9+ presymptomatic), four C9+ animals that developed acute rapidly progressive phenotypes (20-22 weeks old) (Acute) and three NT controls.…”