title: Impairment of autophagy by TTR V30M aggregates: in vivo reversal by TUDCA and curcumin.
abstract: 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.
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, Porto 4200-135, Portugal Unidade de Neurobiologia Molecular, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4200-135, Portugal.
authors.forename: Cristina A
authors.initials: CA
authors.lastname: Teixeira
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, Porto 4200-135, Portugal Unidade de Neurobiologia Molecular, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4200-135, Portugal Departamento de Biologia Molecular, ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto 4050-313, Portugal.
authors.forename: Maria do Rosário
authors.initials: Mdo R
authors.lastname: Almeida
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, Porto 4200-135, Portugal Unidade de Neurobiologia Molecular, IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4200-135, Portugal mjsaraiv@ibmc.up.pt.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D003474:Curcumin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage*
chemical_list: D011228:Prealbumin; D066329:Protein Aggregates; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D003474:Curcumin
keywords: amyloid; autophagy; therapeutics; transthyretin