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

The NYGC ALS Consortium

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1164-1177.e5
JournalCell Reports
Volume29
Issue number5
DOIs
StatePublished - Oct 29 2019

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Retroelements
Oxidative stress
Amyotrophic Lateral Sclerosis
Neuroglia
Oxidative Stress
Chemical activation
Neurodegenerative diseases
Learning algorithms
Neurons
Learning systems
Motor Neurons
Agglomeration
Transcriptome
Neurodegenerative Diseases
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{1b22b56f464b4e98bfabdb3a3c0d7c98,
title = "Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia",
abstract = "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.",
author = "{The NYGC ALS Consortium} and Tam, {Oliver H.} and Rozhkov, {Nikolay V.} and Regina Shaw and Duyang Kim and Isabel Hubbard and Samantha Fennessey and Nadia Propp and Hemali Phatnani and Justin Kwan and Dhruv Sareen and Broach, {James R.} and Zachary Simmons and Ximena Arcila-Londono and Lee, {Edward B.} and {Van Deerlin}, {Vivianna M.} and Shneider, {Neil A.} and Ernest Fraenkel and Ostrow, {Lyle W.} and Frank Baas and Noah Zaitlen and Berry, {James D.} and Andrea Malaspina and Pietro Fratta and Cox, {Gregory A.} and Thompson, {Leslie M.} and Steve Finkbeiner and Efthimios Dardiotis and Miller, {Timothy M.} and Siddharthan Chandran and Suvankar Pal and Eran Hornstein and MacGowan, {Daniel J.} and Terry Heiman-Patterson and Hammell, {Molly G.} and Patsopoulos, {Nikolaos A.} and Oleg Butovsky and Joshua Dubnau and Avindra Nath and Robert Bowser and Matt Harms and Eleonora Aronica and Mary Poss and Jennifer Phillips-Cremins and John Crary and Nazem Atassi and Lange, {Dale J.} and Adams, {Darius J.} and Leonidas Stefanis and Marc Gotkine and Robert Baloh",
year = "2019",
month = "10",
day = "29",
doi = "10.1016/j.celrep.2019.09.066",
language = "English (US)",
volume = "29",
pages = "1164--1177.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
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}

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS : Retrotransposon Activation, Oxidative Stress, and Activated Glia. / The NYGC ALS Consortium.

In: Cell Reports, Vol. 29, No. 5, 29.10.2019, p. 1164-1177.e5.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS

T2 - Retrotransposon Activation, Oxidative Stress, and Activated Glia

AU - The NYGC ALS Consortium

AU - Tam, Oliver H.

AU - Rozhkov, Nikolay V.

AU - Shaw, Regina

AU - Kim, Duyang

AU - Hubbard, Isabel

AU - Fennessey, Samantha

AU - Propp, Nadia

AU - Phatnani, Hemali

AU - Kwan, Justin

AU - Sareen, Dhruv

AU - Broach, James R.

AU - Simmons, Zachary

AU - Arcila-Londono, Ximena

AU - Lee, Edward B.

AU - Van Deerlin, Vivianna M.

AU - Shneider, Neil A.

AU - Fraenkel, Ernest

AU - Ostrow, Lyle W.

AU - Baas, Frank

AU - Zaitlen, Noah

AU - Berry, James D.

AU - Malaspina, Andrea

AU - Fratta, Pietro

AU - Cox, Gregory A.

AU - Thompson, Leslie M.

AU - Finkbeiner, Steve

AU - Dardiotis, Efthimios

AU - Miller, Timothy M.

AU - Chandran, Siddharthan

AU - Pal, Suvankar

AU - Hornstein, Eran

AU - MacGowan, Daniel J.

AU - Heiman-Patterson, Terry

AU - Hammell, Molly G.

AU - Patsopoulos, Nikolaos A.

AU - Butovsky, Oleg

AU - Dubnau, Joshua

AU - Nath, Avindra

AU - Bowser, Robert

AU - Harms, Matt

AU - Aronica, Eleonora

AU - Poss, Mary

AU - Phillips-Cremins, Jennifer

AU - Crary, John

AU - Atassi, Nazem

AU - Lange, Dale J.

AU - Adams, Darius J.

AU - Stefanis, Leonidas

AU - Gotkine, Marc

AU - Baloh, Robert

PY - 2019/10/29

Y1 - 2019/10/29

N2 - 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.

AB - 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.

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U2 - 10.1016/j.celrep.2019.09.066

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