Involvement of glutaredoxin-1 and thioredoxin-1 in -amyloid toxicity and Alzheimer's disease

25 páginas, 10 figuras.Strong evidence indicates oxidative stress in the pathogenesis of Alzheimer's disease (AD). Amyloid (A) has been implicated in both oxidative stress mechanisms and in neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) are antioxidants that can inhibit apoptosis signal-regulating kinase (ASK1). We examined levels of GRX1 and TRX1 in AD brain as well as their effects on A neurotoxicity. We show an increase in GRX1 and a decrease in neuronal TRX1 in AD brains. Using SH-SY5Y cells, we demonstrate that A causes an oxidation of both GRX1 and TRX1, and nuclear export of Daxx, a protein downstream of ASK1. Atoxicity was inhibited by insulin-like growth factor-I (IGF-I) and by overexpressing GRX1 or TRX1. Thus, A neurotoxicity might be mediated by oxidation of GRX1 or TRX1 and subsequent activation of the ASK1 cascade. Deregulation of GRX1 and TRX1 antioxidant systems could be important events in AD pathogenesis.This research was supported by grants from the following Swedish foundations: Hjärnfonden (Swedish Brain Foundation), Gun och Bertil Stohnes Stiftelse, Karolinska Institutets Foundation for geriatric research, Loo and Hans Ostermans Foundation, Åke Wiberg Foundation, Svenska Lundbeck-stiftelsen, Demensförbundet, Alzheimer Foundation; Sweden, Lars Hiertas minnesstiftelse, Gamla Tjänarinnor foundation, Insamlingsstiftelsen för Alzheimer och demenforskning (SADF) and Swedish Brain Power project. AM-V was supported by Swedish Medical Research Council (Projects 03P-14096, 03X-14041, and 13X-10370). AJ was supported by a postdoctoral fellowship EX2003-0390 from the Spanish Ministerio de Educacion, Cultura y Deporte.Peer reviewe

Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients

Purpose: Comprehensive genetic testing for inherited retinal dystrophy (IRD) is challenged by difficult-to-sequence genomic regions, which are often mutational hotspots, such as RPGR ORF15. The purpose of this study was to evaluate the diagnostic contribution of RPGR variants in an unselected IRD patient cohort referred for testing in a clinical diagnostic laboratory. Methods: A total of 5201 consecutive patients were analyzed with a clinically validated next-generation sequencing (NGS)-based assay, including the difficult-to-sequence RPGR ORF15 region. Copy number variant (CNV) detection from NGS data was included. Variant interpretation was performed per the American College of Medical Genetics and Genomics guidelines. Results: A confirmed molecular diagnosis in RPGR was found in 4.5% of patients, 24.0% of whom were females. Variants in ORF15 accounted for 74% of the diagnoses; 29% of the diagnostic variants were in the most difficult-to-sequence central region of ORF15 (c.2470-3230). Truncating variants made up the majority (91%) of the diagnostic variants. CNVs explained 2% of the diagnostic cases, of which 80% were one- or two-exon deletions outside of ORF15. Conclusions: Our findings indicate that high-throughput, clinically validated NGS-based testing covering the difficult-to-sequence region of ORF15, in combination with high-resolution CNV detection, can help to maximize the diagnostic yield for patients with IRD. Translational Relevance: These results demonstrate an accurate and scalable method for the detection of RPGR-related variants, including the difficult-to-sequence ORF15 hotspot, which is relevant given current and emerging therapeutic opportunities.Peer reviewe