Geijtenbeek, Karlijne W;
Janzen, Jolien;
Bury, Aleksandra E;
Sanz-Sanz, Alicia;
Hoebe, Ron A;
Bondulich, Marie K;
Bates, Gillian P;
... Schipper-Krom, Sabine; + view all
(2022)
Reduction in PA28αβ activation in HD mouse brain correlates to increased mHTT aggregation in cell models.
PLOS ONE
, 17
(12)
, Article e0278130. 10.1371/journal.pone.0278130.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Reduction in PA28αβ activation in HD mouse brain correlates to increased mHTT aggregation in cell models |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0278130 |
| Publisher version: | https://doi.org/10.1371/journal.pone.0278130 |
| Language: | English |
| Additional information: | © 2022 Geijtenbeek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | Proteasomes, Mouse models, Native polyacrylamide gel electrophoresis, Transfection, Hippocampus, Huntington disease, Neostriatum, Small interfering RNA |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10166482 |
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