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Elife. 2018 Jul 13;7. pii: e37754. doi: 10.7554/eLife.37754.

Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism.

Author information

1
Department of Biological Sciences, Columbia University, New York, United States.
2
Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, United States.
3
New York Genome Center, New York, United States.
4
Center for Genomics of Neurodegenerative Diseases, New York Genome Center, New York, United States.
5
Department of Neurology, University of Maryland School of Medicine, University of Maryland ALS Clinic, Baltimore, United States.
6
Cedars-Sinai Department of Biomedical Sciences, Board of Governors Regenerative Medicine Institute and Brain Program, Cedars-Sinai Medical Center, Los Angeles, United States.
7
Department of Medicine, University of California, Los Angeles, United States.
8
Department of Biochemistry and Molecular Biology, Penn State Institute for Personalized Medicine, The Pennsylvania State University, Hershey, United States.
9
Department of Neurology, The Pennsylvania State University, Hershey, United States.
10
Department of Neurology, Henry Ford Health System, Detroit, United States.
11
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
12
Department of Neurology, Center for Motor Neuron Biology and Disease, Institute for Genomic Medicine, Columbia University, New York, United States.
13
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States.
14
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, United States.
15
Department of Neurogenetics, Academic Medical Centre, Amsterdam and Leiden University Medical Center, Leiden, Netherlands.
16
Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, United States.
17
ALS Multidisciplinary Clinic, Neuromuscular Division, Department of Neurology, Harvard Medical School, Boston, United States.
18
Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, United States.
19
Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
20
Department of Neurology, Basildon University Hospital, Basildon, United Kingdom.
21
Institute of Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom.
22
The Jackson Laboratory, Bar Harbor, United States.
23
Department of Psychiatry and Human Behavior and Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, United States.
24
Department of Neurobiology and Behavior, School of Biological Sciences, University of California, Irvine, Irvine, United States.
25
Taube/Koret Center for Neurodegenerative Disease Research, Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institute, San Francisco, United States.
26
Department of Neurology and Sensory Organs, University of Thessaly, Thessaly, Greece.
27
Department of Neurology, Washington University in St. Louis, St. Louis, United States.
28
Centre for Clinical Brain Sciences, Anne Rowling Regenerative Neurology Clinic, Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
29
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
30
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, United States.
31
Center for Neurodegenerative Disorders, Department of Neurology, the Lewis Katz School of Medicine, Temple University, Philadelphia, United States.
32
Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
33
Computer Science and Systems Biology Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
34
Division of Genetics in Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
35
Program in Medical and Population Genetics, Broad Institute, Cambridge, United States.
36
Department of Anesthesiology, Stony Brook University, Stony Brook, United States.
37
Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States.
38
Department of Neurology, Columbia University Medical Center, New York, United States.

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these 'like-C9' brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum.

KEYWORDS:

RNA binding proteins; amyotrophic lateral aclerosis; biochemistry; chemical biology; frontotemporal dementia; human; human biology; mRNA splicing; medicine

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