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O1–01–02: Epigenetic modifications reveal an effective use of the protein quality control system to suppress accumulation and toxicity of beta‐amyloid 42 in the secretory pathway in neurons
Author(s) -
Iijima Koichi,
Sekiya Michiko,
MarukoOtake Akiko,
Ando Kanae
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.04.050
Subject(s) - gene knockdown , unfolded protein response , microbiology and biotechnology , biology , proteasome , amyloid beta , epigenetics , endoplasmic reticulum , gene , biochemistry , peptide
chaperone. In support of this theory we have found that mutations in the BRICHOS domain of proSP-C lead to interstitial lung disease with amyloid deposits of SP-C (Willander H., Askarieh G. et al., Proc Natl Acad Sci U S A, 2012). We have recently reported that the BRICHOS domain is an efficient in vitro inhibitor of A b amyloid formation. The proSP-C and the Bri2 BRICHOS domains prevented aggregation and fibril formation of Ab far below stoichiometric amounts of BRICHOS protein, and we could show that the A bwas kept in amonomeric unstructured state in the presence of BRICHOS (Willander H., Presto J. et al., J Biol Chem, 2012).Methods: To further examine BRICHOS effects on Ab in vivo, we have now used transgenic Drosophila melanogaster to study the effects of the BRICHOS domain on Ab aggregation and concomitant neuronal dysfunction.Results: Expression of Ab42 alone in flies results in peptide aggregates detectable with confocal microscopy, reduced life-span and decreased locomotor activity, while expression of proSP-C BRICHOS alone cause no detectable effects compared to wild type flies. Co-expression of proSP-C BRICHOS with Ab42 gives a decreased amount of aggregated peptide, increased life-span as well as improved locomotor activity. The BRICHOS domain is able to prevent Ab in the fly brain from aggregation, and instead keeps Ab soluble. Conclusions: This strongly suggests that the inhibition of Ab 42 aggregation by BRICHOS is accompanied by positive effects on toxicity and neuronal function.