ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 7 (2017): 115, doi:10.1038/s41598-017-00091-1.Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.We are grateful for funding from NIH/NINDS (R01 NS078145, R01 NS090352, and R21 NS091860 to D.A.B., R01 NS066942A and R21 NS096642 to G.M., R01NS023868 and R01NS041170 to S.T.B.), the ALS Therapy Alliance/CVS Pharmacy (to D.A.B. and G.M.) and the ALS Association (to C.F. and J.M.)

Validity and Reliability of the Brazilian Version of the Rapid Estimate of Adult Literacy in Dentistry – BREALD-30

The aim of the present study was to translate, perform the cross-cultural adaptation of the Rapid Estimate of Adult Literacy in Dentistry to Brazilian-Portuguese language and test the reliability and validity of this version.After translation and cross-cultural adaptation, interviews were conducted with 258 parents/caregivers of children in treatment at the pediatric dentistry clinics and health units in Curitiba, Brazil. To test the instrument's validity, the scores of Brazilian Rapid Estimate of Adult Literacy in Dentistry (BREALD-30) were compared based on occupation, monthly household income, educational attainment, general literacy, use of dental services and three dental outcomes.The BREALD-30 demonstrated good internal reliability. Cronbach's alpha ranged from 0.88 to 0.89 when words were deleted individually. The analysis of test-retest reliability revealed excellent reproducibility (intraclass correlation coefficient = 0.983 and Kappa coefficient ranging from moderate to nearly perfect). In the bivariate analysis, BREALD-30 scores were significantly correlated with the level of general literacy (rs = 0.593) and income (rs = 0.327) and significantly associated with occupation, educational attainment, use of dental services, self-rated oral health and the respondent's perception regarding his/her child's oral health. However, only the association between the BREALD-30 score and the respondent's perception regarding his/her child's oral health remained significant in the multivariate analysis.The BREALD-30 demonstrated satisfactory psychometric properties and is therefore applicable to adults in Brazil