Year: 2017
Type: article
Study design: Observational Study
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddx233
Authors: Mercedes Prudencio, Patrick K. Gonzales, Casey N. Cook, Tania F. Gendron, Lillian M. Daughrity, Yuping Song, Mark T.W. Ebbert, Marka van Blitterswijk, Yong-Jie Zhang, Karen Jansen-West, Matthew C. Baker, Michael DeTure, Rosa Rademakers, Kevin B. Boylan, Dennis W. Dickson, Leonard Petrucelli, Christopher D. Link
Institutions: Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: U.S. Department of Defense, ALS Association, Association for Frontotemporal Degeneration, Muscular Dystrophy Association, Johns Hopkins University, Target ALS, Rare Diseases Clinical Research Network, National Institutes of Health, Center for Individualized Medicine, Mayo Clinic, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Robert Packard Center for ALS Research, Johns Hopkins University
Awards: Defining the mechanisms of dipeptide repeat protein toxicity in C9orf72 ALS/FTD, TDP-43, RNA Metabolism, and ALS/FTD Pathology, G261809072, G3432598937, c9RAN proteins as a biomarker for C9ORF72-associated ALS and FTD, Pathophysiology of genetically defined dementia and neurodegeneration: Defining therapeutic targets and pathways, Pathobiology of Neurodegeneration in C9ORF72 repeat expansion, G5455170378, RNA foci in C9FTD/ALS, Silencing C9or72 with rAAV Mediated RNAi, G6636188017, GGGGCC hexanucleotide repeat expansions in neurodegenerative disease, Genetic Discovery and Pathobiology of Frontotemporal Lobar Degeneration and Related TDP-43 Proteinopathies, Expanding insights into FTD disease mechanisms, G893049427, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe)
OpenAlex ID: W2626250818