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

37 Pages Posted: 3 Apr 2019 Sneak Peek Status: Published

See all articles by Oliver H. Tam

Oliver H. Tam

Cold Spring Harbor Laboratory

Nikolay V. Rozhkov

Cold Spring Harbor Laboratory

Regina Shaw

Cold Spring Harbor Laboratory

Duyang Kim

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

Isabel Hubbard

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

Samantha Fennessey

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

Nadia Propp

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

The NYGC ALS Consortium

Delphine Fagegaltier

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

Lyle Ostrow

Johns Hopkins University - Department of Neurology and Neurosurgery; The NYGC ALS Consortium

Hemali Phatnani

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND); The NYGC ALS Consortium

John Ravits

University of California, San Diego (UCSD) - Department of Neurosciences

Josh Dubnau

The NYGC ALS Consortium; State University of New York (SUNY) - Department of Anesthesiology

Molly Gale Hammell

Cold Spring Harbor Laboratory; The NYGC ALS Consortium

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Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several inherited pathogenic mutations have been identified as causative, the vast majority of cases are sporadic with no family history of disease. Thus, for the majority of ALS cases, a specific causal abnormality is not known and the disease may be a product of multiple inter-related pathways contributing to varying degrees in different ALS patients. Using unsupervised machine learning algorithms, we stratified the transcriptomes of 148 ALS decedent cortex tissue samples into three distinct and robust molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 20% of the ALS patient samples exhibited high levels of retrotransposon expression and other signatures of TDP-43 dysfunction. Finally, a third group showed predominant signatures of glial activation (19%). Together these results demonstrate that at least three distinct molecular signatures contribute to ALS disease. While multiple dysregulated components and pathways comprising these clusters have previously been implicated in ALS pathogenesis, unbiased analysis of this large survey demonstrated that sporadic ALS patient tissues can be segregated into distinct molecular subsets.

Keywords: Amyotrophic Lateral Sclerosis, Retrotransposons, Transposable Elements, TDP-43, Neurodegenerative Disease, Neurodegeneration, Genetics & Genomics of ALS

Suggested Citation

Tam, Oliver H. and Rozhkov, Nikolay V. and Shaw, Regina and Kim, Duyang and Hubbard, Isabel and Fennessey, Samantha and Propp, Nadia and Consortium, The NYGC ALS and Fagegaltier, Delphine and Ostrow, Lyle and Phatnani, Hemali and Ravits, John and Dubnau, Josh and Hammell, Molly Gale, Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia (April 2, 2019). Available at SSRN: https://ssrn.com/abstract=3364349 or http://dx.doi.org/10.2139/ssrn.3364349
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Oliver H. Tam

Cold Spring Harbor Laboratory

Cold Spring Harbor, NY 11724
United States

Nikolay V. Rozhkov

Cold Spring Harbor Laboratory

Cold Spring Harbor, NY 11724
United States

Regina Shaw

Cold Spring Harbor Laboratory

Cold Spring Harbor, NY 11724
United States

Duyang Kim

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

New York, NY
United States

Isabel Hubbard

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

New York, NY
United States

Samantha Fennessey

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

New York, NY
United States

Nadia Propp

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

New York, NY
United States

Delphine Fagegaltier

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

New York, NY
United States

Lyle Ostrow

Johns Hopkins University - Department of Neurology and Neurosurgery

Baltimore, MD 21205
United States

The NYGC ALS Consortium

United States

Hemali Phatnani

New York Genome Center - Center for Genomics of Neurodegenerative Diseases (CGND)

New York, NY
United States

The NYGC ALS Consortium

United States

John Ravits

University of California, San Diego (UCSD) - Department of Neurosciences

9500 Gilman Dr.
La Jolla, CA 92093
United States

Josh Dubnau

The NYGC ALS Consortium ( email )

United States

State University of New York (SUNY) - Department of Anesthesiology ( email )

Health Science Center
Stony Brook, NY 11794
United States

Molly Gale Hammell (Contact Author)

Cold Spring Harbor Laboratory ( email )

Cold Spring Harbor, NY 11724
United States

The NYGC ALS Consortium ( email )

United States

No contact information is available for The NYGC ALS Consortium

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