ABSTRACT
Mutations in Fused in Sarcoma (FUS) are present in familial and sporadic cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS is localised in the nucleus where it has important functions in DNA repair. However, in ALS/FTD, mutant FUS mislocalises from the nucleus to the cytoplasm where it forms inclusions, a key pathological hallmark of neurodegeneration. Mutant FUS also inhibits protein import into the nucleus, resulting in defects in nucleocytoplasmic transport. Fragmentation of the neuronal Golgi apparatus, induction of endoplasmic reticulum (ER) stress, and inhibition of ER-Golgi trafficking are also associated with mutant FUS misfolding in ALS. Protein disulphide isomerase (PDI) is an ER chaperone previously shown to be protective against misfolding associated with mutant superoxide dismutase 1 (SOD1) and TAR DNA-binding protein-43 (TDP-43) in cellular and zebrafish models. However, a protective role against mutant FUS in ALS has not been previously described. In this study, we demonstrate that PDI is protective against mutant FUS. In neuronal cell line and primary cultures, PDI restores defects in nuclear import, prevents the formation of mutant FUS inclusions, inhibits Golgi fragmentation, ER stress, ER-Golgi transport defects, and apoptosis. These findings imply that PDI is a new therapeutic target in FUS-associated ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Endoplasmic Reticulum Stress , Frontotemporal Dementia/drug therapy , Mutation , Procollagen-Proline Dioxygenase/pharmacology , Protein Disulfide-Isomerases/pharmacology , RNA-Binding Protein FUS/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Cell Line , Frontotemporal Dementia/metabolism , Frontotemporal Dementia/pathology , Humans , In Vitro Techniques , Models, Theoretical , Protein FoldingABSTRACT
BACKGROUND: Right atrial flutter has a relatively high incidence. It is often symptomatic and can have a poor outcome particularly in case of thrombo-embolic events. AIM OF STUDY: We evaluate the results of radiofrequency catheter ablation for right atrial flutter since the introduction of this technique inour hospital. METHODS: The 28 first patients referred in our institution for atrial flutter and relevant for cavo-tricuspid isthmus ablation were enrolled. Ablation used a 8 mm tip electrode catheter and one or two conventional diagnostic catheters. The goal of ablation was complete bidirectional isthmus block. RESULTS: The first-line success rate was 96 percent with 4 percent early flutter recurrence. The mean duration of radiofrequency current applications was 652 +/- 409 seconds. No complication was observed. CONCLUSION: This results are comparable with the published data and encourage the development of basic ablation procedures and maintenance of rhythmic competence in general hospital inside medical network.
