TY - JOUR
T1 - Disruption of the nascent polypeptide-associated complex leads to reduced polyglutamine aggregation and toxicity
AU - Dublin-Ryan, Leeran B.
AU - Bhadra, Ankan K.
AU - True, Heather L.
N1 - Publisher Copyright:
© 2024 Dublin-Ryan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2024/8
Y1 - 2024/8
N2 - The nascent polypeptide-associate complex (NAC) is a heterodimeric chaperone complex that binds near the ribosome exit tunnel and is the first point of chaperone contact for newly synthesized proteins. Deletion of the NAC induces embryonic lethality in many multi-cellular organisms. Previous work has shown that the deletion of the NAC rescues cells from prion-induced cytotoxicity. This counterintuitive result led us to hypothesize that NAC disruption would improve viability in cells expressing human misfolding proteins. Here, we show that NAC disruption improves viability in cells expressing expanded polyglutamine and also leads to delayed and reduced aggregation of expanded polyglutamine and changes in polyglutamine aggregate morphology. Moreover, we show that NAC disruption leads to changes in de novo yeast prion induction. These results indicate that the NAC plays a critical role in aggregate organization as a potential therapeutic target in neurodegenerative disorders.
AB - The nascent polypeptide-associate complex (NAC) is a heterodimeric chaperone complex that binds near the ribosome exit tunnel and is the first point of chaperone contact for newly synthesized proteins. Deletion of the NAC induces embryonic lethality in many multi-cellular organisms. Previous work has shown that the deletion of the NAC rescues cells from prion-induced cytotoxicity. This counterintuitive result led us to hypothesize that NAC disruption would improve viability in cells expressing human misfolding proteins. Here, we show that NAC disruption improves viability in cells expressing expanded polyglutamine and also leads to delayed and reduced aggregation of expanded polyglutamine and changes in polyglutamine aggregate morphology. Moreover, we show that NAC disruption leads to changes in de novo yeast prion induction. These results indicate that the NAC plays a critical role in aggregate organization as a potential therapeutic target in neurodegenerative disorders.
UR - http://www.scopus.com/inward/record.url?scp=85201353255&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0303008
DO - 10.1371/journal.pone.0303008
M3 - Article
C2 - 39146256
AN - SCOPUS:85201353255
SN - 1932-6203
VL - 19
JO - PloS one
JF - PloS one
IS - 8 AUGUST
M1 - e0303008
ER -