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.
|Number of pages||11|
|Journal||Human Molecular Genetics|
|State||Published - Sep 1 2017|
Bibliographical noteFunding Information:
We are grateful to all patients who donated tissues.This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [R01NS063964 (C.D.L.); R21NS089979 (K.B.B., T.F.G.); R35NS097273 (L.P.); R21NS084528 (L.P.); P01NS084974 (L.P., K.B.B., R.R.); P01NS099114 (L.P.); R01NS088689 (L.P.); R01NS093865 (L.P.); R35NS097261 (R.R.); R01NS080882 (R.R.)]; Department of Defense (ALSRP AL130125, L.P.); Mayo Clinic Foundation (L.P.); Mayo Clinic Center for Individualized Medicine (K.B.B., T.F.G., L.P.); Amyotrophic Lateral Sclerosis Association (K.B.B., T.F.G., L.P., M.P.); Robert Packard Center for ALS Research at Johns Hopkins (L.P.), Target ALS (L.P.); Association for Frontotemporal Degeneration (L.P.); Muscular Dystrophy Association (#416137, T.F.G.); Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Clinical Research Fellowship (U54 NS092091, M.V.B.). CReATe is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS). CReATe is funded through collaboration between NCATS and the NINDS. Funding to pay the Open Access publication charges for this article was provided by Mayo Clinic Foundation
© The Author 2017.
ASJC Scopus subject areas
- Molecular Biology