TY - JOUR
T1 - Reduction in PA28αβ activation in HD mouse brain correlates to increased mHTT aggregation in cell models
AU - Geijtenbeek, Karlijne W.
AU - Janzen, Jolien
AU - Bury, Aleksandra E.
AU - Sanz-Sanz, Alicia
AU - Hoebe, Ron A.
AU - Bondulich, Marie K.
AU - Bates, Gillian P.
AU - Reits, Eric A. J.
AU - Schipper-Krom, Sabine
N1 - Funding Information:
This work was funded by CHDI and Campagneteam Huntington. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2022 Geijtenbeek 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 - 2022/12
Y1 - 2022/12
N2 - Huntington's disease is an autosomal dominant heritable disorder caused by an expanded CAG trinucleotide repeat at the N-terminus of the Huntingtin (HTT) gene. Lowering the levels of soluble mutant HTT protein prior to aggregation through increased degradation by the proteasome would be a therapeutic strategy to prevent or delay the onset of disease. Native PAGE experiments in HdhQ150 mice and R6/2 mice showed that PA28αβ disassembles from the 20S proteasome during disease progression in the affected cortex, striatum and hippocampus but not in cerebellum and brainstem. Modulating PA28αβ activated proteasomes in various in vitro models showed that PA28αβ improved polyQ degradation, but decreased the turnover of mutant HTT. Silencing of PA28αβ in cells lead to an increase in mutant HTT aggregates, suggesting that PA28αβ is critical for overall proteostasis, but only indirectly affects mutant HTT aggregation.
AB - Huntington's disease is an autosomal dominant heritable disorder caused by an expanded CAG trinucleotide repeat at the N-terminus of the Huntingtin (HTT) gene. Lowering the levels of soluble mutant HTT protein prior to aggregation through increased degradation by the proteasome would be a therapeutic strategy to prevent or delay the onset of disease. Native PAGE experiments in HdhQ150 mice and R6/2 mice showed that PA28αβ disassembles from the 20S proteasome during disease progression in the affected cortex, striatum and hippocampus but not in cerebellum and brainstem. Modulating PA28αβ activated proteasomes in various in vitro models showed that PA28αβ improved polyQ degradation, but decreased the turnover of mutant HTT. Silencing of PA28αβ in cells lead to an increase in mutant HTT aggregates, suggesting that PA28αβ is critical for overall proteostasis, but only indirectly affects mutant HTT aggregation.
UR - https://www.scopus.com/pages/publications/85144636423
U2 - 10.1371/journal.pone.0278130
DO - 10.1371/journal.pone.0278130
M3 - Article
C2 - 36574405
SN - 1932-6203
VL - 17
SP - e0278130
JO - PLoS ONE
JF - PLoS ONE
IS - 12 December
M1 - e0278130
ER -