2025-05-05 バッファロー大学 (UB)
A comparison of healthy human neurons with neurons of a Huntington’s disease patient where GSK3ß and ERK1 were upregulated. Credit: Krzystek and Gunawardena/University at Buffalo
<関連情報>
- https://www.buffalo.edu/news/releases/2025/05/protein-mitigates-huntingtons-disease.html
- https://www.nature.com/articles/s41419-025-07524-0
- https://academic.oup.com/hmg/article/24/25/7182/2384460
ハンチントン病の神経機能障害と細胞死におけるハンチンチンのGSK3βとERK1依存性リン酸化の相反する役割 Opposing roles for GSK3β and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington’s disease
Thomas J. Krzystek,Rasika Rathnayake,Jia Zeng,Jing Huang,Gary Iacobucci,Michael C. Yu & Shermali Gunawardena
Cell Death & Disease Published:22 April 2025
DOI:https://doi.org/10.1038/s41419-025-07524-0
Abstract
Huntington’s disease (HD) is a devastating neurodegenerative disorder that manifests from an N-terminal polyQ-expansion (>35) in the Huntingtin (HTT) gene leading to axonal degeneration and significant neuronal death. Despite evidence for a scaffolding role for HTT in membrane-related processes such as endocytosis, vesicle transport, and vesicle fusion, it remains unclear how polyQ-expansion alters membrane binding during these processes. Using quantitative Mass Spectrometry-based proteomics on HTT-containing light vesicle membranes isolated from healthy and HD iPSC-derived neurons, we found significant changes in the proteome and kinome of signal transduction, neuronal translation, trafficking, and axon guidance-related processes. Through a combination of in vitro kinase assays, Drosophila genetics, and pharmacological inhibitors, we identified that GSK3β and ERK1 phosphorylate HTT and that these events play distinct and opposing roles during HD with inhibition of GSK3β decreasing polyQ-mediated axonal transport defects and neuronal cell death, while inhibition of ERK enhancing these phenotypes. Together, this work proposes two novel pathways in which GSK3β phosphorylation events exacerbate and ERK phosphorylation events mitigate HD-dependent neuronal dysfunction highlighting a highly druggable pathway for targeted therapeutics using already available small molecules.
ハンチンチンはin vivoにおいてRab含有小胞のサブセットの軸索輸送を異なって制御する Huntingtin differentially regulates the axonal transport of a sub-set of Rab-containing vesicles in vivo
Joseph A. White, II , Eric Anderson , Katherine Zimmerman , Kan Hong Zheng , Roza Rouhani , Shermali Gunawardena
Human Molecular Genetics Published:08 October 2015
DOI:https://doi.org/10.1093/hmg/ddv415
Abstract
Loss of huntingtin (HTT), the Huntington’s disease (HD) protein, was previously shown to cause axonal transport defects. Within axons, HTT can associate with kinesin-1 and dynein motors either directly or via accessory proteins for bi-directional movement. However, the composition of the vesicle-motor complex that contains HTT during axonal transport is unknown. Here we analyze the in vivo movement of 16 Rab GTPases within Drosophila larval axons and show that HTT differentially influences the movement of a particular sub-set of these Rab-containing vesicles. While reduction of HTT perturbed the bi-directional motility of Rab3 and Rab19-containing vesicles, only the retrograde motility of Rab7-containing vesicles was disrupted with reduction of HTT. Interestingly, reduction of HTT stimulated the anterograde motility of Rab2-containing vesicles. Simultaneous dual-view imaging revealed that HTT and Rab2, 7 or 19 move together during axonal transport. Collectively, our findings indicate that HTT likely influences the motility of different Rab-containing vesicles and Rab-mediated functions. These findings have important implications for our understanding of the complex role HTT plays within neurons normally, which when disrupted may lead to neuronal death and disease.
