@article{8b2d5c291f894df19c9d12c078c2df6c,
title = "Formation of toxic oligomers of polyQ-expanded Huntingtin by prion-mediated cross-seeding",
abstract = "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 orthogonal 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.",
keywords = "cross-seeding, Huntington's disease, neurodegeneration, oligomers, optogenetics, polyQ, prion, protein aggregation, proteostasis, Rnq1",
author = "Gropp, {Michael H.M.} and Klaips, {Courtney L.} and Hartl, {F. Ulrich}",
note = "Funding Information: We thank Clifford Brangwynne (Princeton University, USA) for providing plasmids. Silvia G{\"a}rtner, Romy Lange, and Nadine Wischnewski are acknowledged for expert technical assistance. We thank the staff of the MPIB core facility for competent technical support with MS experiments. We thank Cole Sitron for critically reading the manuscript and Michele Vendruscolo for discussion. The research leading to these results has received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) (F.U.H.). M.H.M.G. was supported by a DFG fellowship through the Graduate School of Quantitative Biosciences Munich (QBM). C.L.K. acknowledges funding by the Alexander von Humboldt Foundation (Postdoctoral Fellowship 3.1-USA/1162753 HFST-P). M.H.M.G. planned and performed all experiments and analyzed the data. F.U.H. conceived the project and participated in data interpretation together with the other authors. C.L.K. acted as co-supervisor. M.H.M.G. C.L.K. and F.U.H. wrote the paper. F.U.H. is a member of the Molecular Cell advisory board. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. Funding Information: We thank Clifford Brangwynne (Princeton University, USA) for providing plasmids. Silvia G{\"a}rtner, Romy Lange, and Nadine Wischnewski are acknowledged for expert technical assistance. We thank the staff of the MPIB core facility for competent technical support with MS experiments. We thank Cole Sitron for critically reading the manuscript and Michele Vendruscolo for discussion. The research leading to these results has received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation ) under Germany{\textquoteright}s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology ( EXC 2145 SyNergy—ID 390857198 ) (F.U.H.). M.H.M.G. was supported by a DFG fellowship through the Graduate School of Quantitative Biosciences Munich (QBM). C.L.K. acknowledges funding by the Alexander von Humboldt Foundation (Postdoctoral Fellowship 3.1- USA/1162753 HFST-P). Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = nov,
day = "17",
doi = "10.1016/j.molcel.2022.09.031",
language = "English",
volume = "82",
pages = "4290--4306.e11",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "CELL PRESS",
number = "22",
}