| First Author | Geijtenbeek KW | Year | 2022 |
| Journal | PLoS One | Volume | 17 |
| Issue | 12 | Pages | e0278130 |
| PubMed ID | 36574405 | Mgi Jnum | J:340441 |
| Mgi Id | MGI:7413582 | Doi | 10.1371/journal.pone.0278130 |
| Citation | Geijtenbeek KW, et al. (2022) Reduction in PA28alphabeta activation in HD mouse brain correlates to increased mHTT aggregation in cell models. PLoS One 17(12):e0278130 |
| abstractText | 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 PA28alphabeta disassembles from the 20S proteasome during disease progression in the affected cortex, striatum and hippocampus but not in cerebellum and brainstem. Modulating PA28alphabeta activated proteasomes in various in vitro models showed that PA28alphabeta improved polyQ degradation, but decreased the turnover of mutant HTT. Silencing of PA28alphabeta in cells lead to an increase in mutant HTT aggregates, suggesting that PA28alphabeta is critical for overall proteostasis, but only indirectly affects mutant HTT aggregation. |
