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 - Raj, Towfique
N1 - Publisher Copyright:
© 2019 The Author(s)
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.
KW - TDP-43
KW - amyotrophic lateral sclerosis
KW - genetics and genomics of ALS
KW - neurodegeneration
KW - neurodegenerative disease
KW - retrotransposons
KW - transposable elements
UR - http://www.scopus.com/inward/record.url?scp=85074157599&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.09.066
DO - 10.1016/j.celrep.2019.09.066
M3 - Article
C2 - 31665631
AN - SCOPUS:85074157599
SN - 2211-1247
VL - 29
SP - 1164-1177.e5
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -