Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia
Document Type
Article
Abstract
© 2019 The Author(s) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displays hallmarks of oxidative and proteotoxic stress. Another 19% of the samples shows predominant signatures of glial activation. Finally, a third group (20%) exhibits high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrate that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo.
Keywords
amyotrophic lateral sclerosis, genetics and genomics of ALS, neurodegeneration, neurodegenerative disease, retrotransposons, TDP-43, transposable elements
Publication Date
10-29-2019
Publication Title
Cell Reports
E-ISSN
22111247
Volume
29
Issue
5
First Page
1164
Last Page
1177.e5
PubMed ID
31665631
Digital Object Identifier (DOI)
10.1016/j.celrep.2019.09.066
Recommended Citation
Tam, Oliver H.; Rozhkov, Nikolay V.; Shaw, Regina; Kim, Duyang; Hubbard, Isabel; Fennessey, Samantha; Propp, Nadia; Phatnani, Hemali; Kwan, Justin; Sareen, Dhruv; Broach, James R.; Simmons, Zachary; Arcila-Londono, Ximena; Lee, Edward B.; Van Deerlin, Vivianna M.; Shneider, Neil A.; Fraenkel, Ernest; Ostrow, Lyle W.; Baas, Frank; Zaitlen, Noah; Berry, James D.; Malaspina, Andrea; Fratta, Pietro; Cox, Gregory A.; Thompson, Leslie M.; Finkbeiner, Steve; Dardiotis, Efthimios; Miller, Timothy M.; Chandran, Siddharthan; Pal, Suvankar; and Hornstein, Eran, "Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia" (2019). Translational Neuroscience. 540.
https://scholar.barrowneuro.org/neurobiology/540