Details

Autor(en) / Beteiligte

• Geijtenbeek, Karlijne W
• Janzen, Jolien
• Bury, Aleksandra E
• Sanz-Sanz, Alicia
• Hoebe, Ron A
• Bondulich, Marie K
• Bates, Gillian P
• Reits, Eric A J
• Schipper-Krom, Sabine
• Kampinga, Harm H.

Titel

Reduction in PA28αβ activation in HD mouse brain correlates to increased mHTT aggregation in cell models

Ist Teil von

• PloS one, 2022-12, Vol.17 (12), p.e0278130-e0278130

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2022

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.