<i>CASP8</i> intronic expansion identified by poly-glycine-arginine pathology increases Alzheimer’s disease risk
Abstract
Alzheimer’s disease (AD) affects more than 10% of the population ≥65 y of age, but the underlying biological risks of most AD cases are unclear. We show anti-poly-glycine-arginine (a-polyGR) positive aggregates frequently accumulate in sporadic AD autopsy brains (45/80 cases). We hypothesize that these aggregates are caused by one or more polyGR-encoding repeat expansion mutations. We developed a CRISPR/deactivated-Cas9 enrichment strategy to identify candidate GR-encoding repeat expansion mutations directly from genomic DNA isolated from a-polyGR(+) AD cases. Using this approach, we isolated an interrupted (GGGAGA) n intronic expansion within a SINE-VNTR-Alu element in CASP8 ( CASP8 -GGGAGA EXP ). Immunostaining using a-polyGR and locus-specific C-terminal antibodies demonstrate that the CASP8 -GGGAGA EXP expresses hybrid poly(GR)n(GE)n(RE)n proteins that accumulate in CASP8 -GGGAGA EXP (+) AD brains. In cells, expression of CASP8 -GGGAGA EXP minigenes leads to increased p-Tau (Ser202/Thr205) levels. Consistent with other types of repeat-associated non-AUG (RAN) proteins, poly(GR)n(GE)n(RE)n protein levels are increased by stress. Additionally, levels of these stress-induced proteins are reduced by metformin. Association studies show specific aggregate promoting interrupted CASP8 -GGGAGA EXP sequence variants found in ~3.6% of controls and 7.5% AD cases increase AD risk [ CASP8 -GGGAGA-AD-R1; OR 2.2, 95% CI (1.5185 to 3.1896), P = 3.1 × 10 −5 ]. Cells transfected with a high-risk CASP8 -GGGAGA-AD-R1 variant show increased toxicity and increased levels of poly(GR)n(GE)n(RE)n aggregates. Taken together, these data identify polyGR(+) aggregates as a frequent and unexpected type of brain pathology in AD and CASP8 -GGGAGA-AD-R1 alleles as a relatively common AD risk factor. Taken together, these data support a model in which CASP8 -GGGAGA EXP alleles combined with stress increase AD risk.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (30)
Lien Nguyen
Ramadan Ajredini
Center for NeuroGenetics, College of Medicine, University of Florida
Shu Guo
Shenzhen Institute for Quantum Science and Engineering, Department of Chemistry, and Department of Physics
Lisa E. L. Romano
Center for NeuroGenetics, College of Medicine, University of Florida
Rodrigo F. Tomas
Center for NeuroGenetics, College of Medicine, University of Florida
Logan R. Bell
Center for NeuroGenetics, College of Medicine, University of Florida
Paul T. Ranum
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, University of Pennsylvania
Tao Zu
Center for NeuroGenetics, College of Medicine, University of Florida
Monica Bañez Coronel
Center for NeuroGenetics, College of Medicine, University of Florida
Chase P. Kelley
Center for NeuroGenetics, College of Medicine, University of Florida
Javier Redding-Ochoa
Department of Pathology, The Johns Hopkins University School of Medicine
Evangelos Nizamis
Division of Medical Genetics School of Medicine, University of Washington
Alexandra Melloni
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital
Theresa R. Connors
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital
Angelica Gaona
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital
Kiruphagaran Thangaraju
Center for NeuroGenetics, College of Medicine, University of Florida
Olga Pletnikova
Department of Pathology, The Johns Hopkins University School of Medicine
H. Brent Clark
Department of Laboratory Medicine and Pathology, University of Minnesota
Beverly L. Davidson
Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, University of Pennsylvania
Anthony T. Yachnis
Center for NeuroGenetics, College of Medicine, University of Florida
Todd E. Golde
Center for Translation Research in Neurodegenerative Disease, College of Medicine, University of Florida
XiangYang Lou
Department of Biostatistics, University of Florida
Eric T. Wang
Center for NeuroGenetics, College of Medicine, University of Florida
Alan E. Renton
Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Alison Goate
Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
Paul N. Valdmanis
Division of Medical Genetics School of Medicine, University of Washington
Stefan Prokop
Center for NeuroGenetics, College of Medicine, University of Florida
Juan C. Troncoso
Department of Pathology, The Johns Hopkins University School of Medicine
Bradley T. Hyman
Laura P. W. Ranum
Center for NeuroGenetics, College of Medicine, University of Florida