RESUMEN
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in C9orf72 (C9-HRE). While RNA and dipeptide repeats produced by C9-HRE disrupt nucleocytoplasmic transport, the proteins that become redistributed remain unknown. Here, we utilized subcellular fractionation coupled with tandem mass spectrometry and identified 126 proteins, enriched for protein translation and RNA metabolism pathways, which collectively drive a shift toward a more cytosolic proteome in C9-HRE cells. Among these was eRF1, which regulates translation termination and nonsense-mediated decay (NMD). eRF1 accumulates within elaborate nuclear envelope invaginations in patient induced pluripotent stem cell (iPSC) neurons and postmortem tissue and mediates a protective shift from protein translation to NMD-dependent mRNA degradation. Overexpression of eRF1 and the NMD driver UPF1 ameliorate C9-HRE toxicity in vivo. Our findings provide a resource for proteome-wide nucleocytoplasmic alterations across neurodegeneration-associated repeat expansion mutations and highlight eRF1 and NMD as therapeutic targets in C9orf72-associated ALS and/or FTD.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Proteínas de Drosophila/genética , Demencia Frontotemporal/genética , Neuronas/metabolismo , Degradación de ARNm Mediada por Codón sin Sentido/genética , Factores de Terminación de Péptidos/genética , ARN Mensajero/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteína C9orf72/metabolismo , Fraccionamiento Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Demencia Frontotemporal/metabolismo , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas , Membrana Nuclear , Terminación de la Cadena Péptídica Traduccional/genética , Factores de Terminación de Péptidos/metabolismo , Biosíntesis de Proteínas , Proteoma , Fracciones Subcelulares , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Professional basketball players in the National Basketball Association (NBA) subject their lower extremities to significant repetitive loading during both regular-season and off-season training. Little is known about the incidence of lower extremity bony stress injuries and their impact on return to play and performance in these athletes. HYPOTHESIS: Stress injuries of the lower extremity will have significant impact on performance. STUDY DESIGN: Case series. LEVEL OF EVIDENCE: Level 4. METHODS: All bony stress injuries from 2005 to 2015 were identified from the NBA. Number of games missed due to injury and performance statistics were collected from 2 years prior to injury to 2 years after the injury. A linear regression analysis was performed to determine the impact of injury for players who returned to sport. RESULTS: A total of 76 lower extremity bony stress injuries involving 75 NBA players (mean age, 25.4 ± 4.1 years) were identified. Fifty-five percent (42/76) involved the foot, and most injuries occurred during the regular season (82.9%, 63/76), with half occurring within the first 6 weeks. Among players who sustained a fifth metatarsal stress fracture, 42.9% were unable to return to professional play. Players who sustained stress injuries had reduced play performance, specifically related to number of games played ( P = 0.014) and number of steals per game ( P = 0.004). Players who had surgery had significantly better performance at 2 years than those who were managed nonoperatively, independent of the type of injury (ß = 4.561; 95% CI, 1.255-7.868). CONCLUSION: Lower extremity bony stress injuries may significantly affect both short- and long-term player performance and career length. Stress injuries result in decreased player performance, and surgical intervention results in improved performance metrics compared with those treated using conservative methods. CLINICAL RELEVANCE: Stress injuries result in decreased player performance, and surgical intervention results in improved performance metrics.
