ATF6 activation reduces the secretion and extracellular aggregation of destabilized variants of an amyloidogenic protein.

ABSTRACT: Systemic amyloidoses result from the aberrant secretion of destabilized, amyloidogenic proteins to the serum where they aggregate into proteotoxic soluble aggregates and amyloid fibrils. Few therapeutic approaches exist to attenuate extracellular pathologic aggregation of amyloidogenic proteins, necessitating the development of new strategies to intervene in these devastating disorders. We show that stress-independent activation of the Unfolded Protein Response-associated transcription factor ATF6 increases ER quality control stringency for the amyloidogenic protein transthyretin (TTR), preferentially reducing secretion of disease-associated TTR variants to an extent corresponding to the variants' destabilization of the TTR tetramer. This decrease in destabilized TTR variant secretion atte

SUBMITTER: Chen JJ 

PROVIDER: S-EPMC4254654 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature