CASP8 intronic expansion identified by poly-glycine-arginine pathology increases Alzheimer's disease risk

• 成果类型: Article
• 署名作者: Nguyen, Lien; Ajredini, Ramadan; Guo, Shu; Romano, Lisa E. L.; Tomas, Rodrigo F.; Bell, Logan R.; Ranum, Paul T.; Zu, Tao; Coronel, Monica Banez; Kelley, Chase P.; Redding-Ochoa, Javier; Nizamis, Evangelos; Melloni, Alexandra; Connors, Theresa R.; Gaona, Angelica; Thangaraju, Kiruphagaran; Pletnikova, Olga; Clark, H. Brent; Davidson, Beverly L.; Yachnis, Anthony T.; Golde, Todd E.; Lou, Xiangyang; Wang, Eric T.; Renton, Alan E.; Goate, Alison; Valdmanis, Paul N.; Prokop, Stefan; Troncoso, Juan C.; Hyman, Bradley T.; Ranum, Laura P. W.
• 署名单位: State University System of Florida; University of Florida; State University System of Florida; University of Florida; State University System of Florida; University of Florida; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Johns Hopkins University; University of Washington; University of Washington Seattle; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Minnesota System; University of Minnesota Twin Cities; State University System of Florida; University of Florida; State University System of Florida; University of Florida; State University System of Florida; University of Florida; State University System of Florida; University of Florida; State University System of Florida; University of Florida; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; State University System of Florida; University of Florida; State University System of Florida; University of Florida
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13169
• DOI: 10.1073/pnas.2416885122
• 发表日期: 2025-02-18
• 关键词: amyotrophic-lateral-sclerosis; dipeptide-repeat proteins; hexanucleotide repeat; ran translation; frontotemporal dementia; oxidative stress; ggggcc repeat; c9orf72; retrotransposon; thapsigargin

摘要

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 similar to 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 x 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.