Journal
ACTA NEUROPATHOLOGICA
Volume 134, Issue 5, Pages 715-728Publisher
SPRINGER
DOI: 10.1007/s00401-017-1760-4
Keywords
Amyotrophic lateral sclerosis; C9orf72; DNA methylation; Epigenetic modification; SERPINA1; Transcriptome regulation
Categories
Funding
- National Institutes of Health/National Institute on Aging [AG16574-17 J PILOT]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21NS074121, P01NS084974]
- Mayo Clinic Center for Individualized Medicine
- ALS Association
- Donors Cure Foundation
- Robert Packard Center for ALS Research at Johns Hopkins
- ALS Canada
- Brain Canada
- Amyotrophic Lateral Sclerosis Association
- Canadian Institutes of Health Research
- Siragusa Foundation
- Robert and Clarice Smith & Abigail Van Buren Alzheimer's Disease Research Foundation
- PhRMA Foundation Research Starter grant
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We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive multi-omic analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis.
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