非表示:
キーワード:
INCLUSION-BODY FORMATION; POLYGLUTAMINE AGGREGATION;
SACCHAROMYCES-CEREVISIAE; NEURODEGENERATIVE DISEASES; HETEROLOGOUS
MODULES; PROTEIN AGGREGATION; EXPANSION PROTEINS; MUTANT HUNTINGTIN;
AMYLOID-BETA; PSI+ PRIONBiochemistry & Molecular Biology; Cell Biology;
要旨:
Manifestation of aggregate pathology in Huntington's disease is thought to be facilitated by a preferential vulnerability of affected brain cells to age-dependent proteostatic decline. To understand how specific cellular backgrounds may facilitate pathologic aggregation, we utilized the yeast model in which polyQ-expanded Huntingtin forms aggregates only when the endogenous prion-forming protein Rnq1 is in its amyloid-like prion [PIN+] conformation. We employed optogenetic clustering of polyQ protein as an orthog-onal method to induce polyQ aggregation in prion-free [pin-] cells. Optogenetic aggregation circumvented the prion requirement for the formation of detergent-resistant polyQ inclusions but bypassed the formation of toxic polyQ oligomers, which accumulated specifically in [PIN+] cells. Reconstitution of aggregation in vitro suggested that these polyQ oligomers formed through direct templating on Rnq1 prions. These findings shed light on the mechanism of prion-mediated formation of oligomers, which may play a role in triggering polyQ pathology in the patient brain.
