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
N1 - Funding Information:
We wish to thank Y. Jin for helpful discussions, the Target ALS Human Postmortem Tissue Core for providing post-mortem brain samples and slides, the CSHL Sequencing Facility (supported by an NIH Cancer Center support grant 5P30CA045508 ) for additional sequencing support, the CSHL Histology Core Facility (partially supported by NIH support grant 5P30CA045508 ) for performing the histology and IHC staining, the CSHL monoclonal antibody collection (supported by an NIH Cancer Center support grant 5P30CA045508 ) for the anti alpha-tubulin mouse monoclonal antibody (clone DM1A), and the Harms laboratory for performing repeat-primed PCR to identify C9ORF72 expansions in the Target ALS samples. Schematic images were adapted with permission from Servier Medical Art ( https://smart.servier.com ). This work was supported by grants from the Chan Zuckerberg Initiative ( DAF2018-191863 ), the Ride For Life Foundation , the Rita Allen Foundation of which M.H. is a scholar, the O’Neil Charitable Trust , the NIH/NINDS ( 5R21NS088449 and R01NS091748 ), and the NIH/NIA ( R01AG057338 ). All NYGC ALS Consortium activities are supported by the ALS Association ( 15-LGCA-234 ) and the Tow Foundation .
Funding Information:
We wish to thank Y. Jin for helpful discussions, the Target ALS Human Postmortem Tissue Core for providing post-mortem brain samples and slides, the CSHL Sequencing Facility (supported by an NIH Cancer Center support grant 5P30CA045508) for additional sequencing support, the CSHL Histology Core Facility (partially supported by NIH support grant 5P30CA045508) for performing the histology and IHC staining, the CSHL monoclonal antibody collection (supported by an NIH Cancer Center support grant 5P30CA045508) for the anti alpha-tubulin mouse monoclonal antibody (clone DM1A), and the Harms laboratory for performing repeat-primed PCR to identify C9ORF72 expansions in the Target ALS samples. Schematic images were adapted with permission from Servier Medical Art (https://smart.servier.com). This work was supported by grants from the Chan Zuckerberg Initiative (DAF2018-191863), the Ride For Life Foundation, the Rita Allen Foundation of which M.H. is a scholar, the O'Neil Charitable Trust, the NIH/NINDS (5R21NS088449 and R01NS091748), and the NIH/NIA (R01AG057338). All NYGC ALS Consortium activities are supported by the ALS Association (15-LGCA-234) and the Tow Foundation. O.H.T. M.G.H. and J.D. designed the study. N.V.R. designed and performed the experiments identifying TDP-43 targets in SH-SY5Y cells. R.S. designed and performed the experiments on the UCSD ALS patient samples. J.R. provided the UCSD ALS patient samples and associated clinical and diagnostic data. In the NYGC ALS Consortium, members contributed ALS patient samples and clinical information. D.K. curated de-identified clinical data and C9orf72 genotype information. I.H. and N.P. coordinated study materials and processed samples for sequencing. S.F. oversees Consortium resources and data distribution. D.F. and H.P. designed the methodology, reviewed sample preparation and data quality, and coordinated the research activity of NYGC ALS Consortium postmortem core RNA-seq experiments. B.T.H. supervised the neuropathological analysis of the immunohistochemical staining results. L.W.O. coordinated the post-mortem tissue, slide, and data collection through the Target ALS Multicenter Post-Mortem Tissue Core and assisted in analysis of the immunohistochemical staining results. O.H.T. and M.G.H. analyzed the data. All authors contributed to the interpretation, writing, and editing of the manuscript. The authors declare no competing interests.
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.
UR - http://www.scopus.com/inward/record.url?scp=85074157599&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.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 -