4.8 Article

Formation of toxic oligomers of polyQ-expanded Huntingtin by prion-mediated cross-seeding

Journal

MOLECULAR CELL
Volume 82, Issue 22, Pages 4290-+

Publisher

CELL PRESS
DOI: 10.1016/j.molcel.2022.09.031

Keywords

-

Funding

  1. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy [EXC 2145, 390857198]
  2. DFG fellowship through the Graduate School of Quantitative Biosciences Munich
  3. Alexander von Humboldt Foundation [3.1-USA/1162753 HFST-P]

Ask authors/readers for more resources

This study investigated the mechanism of aggregate pathology in Huntington's disease using a yeast model, and revealed the role of cellular vulnerability to age-dependent proteostatic decline. The optogenetic aggregation of polyQ protein bypassed the requirement of prion-forming protein for aggregate formation, shedding light on the prion-mediated oligomer formation mechanism.
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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available