Impairment of autophagy by TTR V30M aggregates: in vivo reversal by TUDCA and curcumin

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Teixeira, CA (Author) Other; Almeida, MR (Author) ICBAS; Maria Joao Saraiva (Author) FCUP

Journal

Title: Clinical Science

Vol. 130

Pages: 1665-1675

ISSN: 0143-5221

Publisher: PORTLAND PRESS LTD

Indexing

ISI Web of Knowledge - 11 Citations

Scopus - 10 Citations

Other information

Authenticus ID: P-00M-GCH

DOI: 10.1042/cs20160075

Abstract (EN): Transthyretin (TTR)-related amyloidoses are diseases characterized by extracellular deposition of amyloid fibrils and aggregates in tissues composed of insoluble misfolded TTR that becomes toxic. Previous studies have demonstrated the ability of small compounds in preventing and reversing TTR V30M deposition in transgenic mice gastrointestinal (GI) tract as well as lowering biomarkers associated with cellular stress and apoptotic mechanisms. In the present study we aimed to study TTR V30M aggregates effect in autophagy, a cellular mechanism crucial for cell survival that has been implicated in the development of several neurodegenerative diseases. We were able to demonstrate in cell culture that TTR V30M aggregates cause a partial impairment of the autophagic machinery as shown by p62 accumulation, whereas early steps of the autophagic flux remain unaffected as shown by autophagosome number evaluation and LC3 turnover assay. Our studies performed in TTR V30M transgenic animals demonstrated that tauroursodeoxycholic acid (TUDCA) and curcumin effectively reverse p62 accumulation in the GI tract pointing to the ability of both compounds to modulate autophagy additionally to mitigate apoptosis. Overall, our in vitro and in vivo studies establish an association between TTR V30M aggregates and autophagy impairment and suggest the use of autophagy modulators as an additional and alternative therapeutic approach for the treatment of TTR V30M-related amyloidosis.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11