Golgi Outpost Synthesis Impaired by Toxic Polyglutamine Proteins Contributes to Dendritic Pathology in Neurons

Chang Geon Chung, Min Jee Kwon, Keun Hye Jeon, Do Young Hyeon, Myeong Hoon Han, Jeong Hyang Park, In Jun Cha, Jae Ho Cho, Kunhyung Kim, Sangchul Rho, Gyu Ree Kim, Hyobin Jeong, Jae Won Lee, Tae Soo Kim, Keetae Kim, Kwang Pyo Kim, Michael D. Ehlers, Daehee Hwang, Sung Bae Lee

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Dendrite aberration is a common feature of neurodegenerative diseases caused by protein toxicity, but the underlying mechanisms remain largely elusive. Here, we show that nuclear polyglutamine (polyQ) toxicity resulted in defective terminal dendrite elongation accompanied by a loss of Golgi outposts (GOPs) and a decreased supply of plasma membrane (PM) in Drosophila class IV dendritic arborization (da) (C4 da) neurons. mRNA sequencing revealed that genes downregulated by polyQ proteins included many secretory pathway-related genes, including COPII genes regulating GOP synthesis. Transcription factor enrichment analysis identified CREB3L1/CrebA, which regulates COPII gene expression. CrebA overexpression in C4 da neurons restores the dysregulation of COPII genes, GOP synthesis, and PM supply. Chromatin immunoprecipitation (ChIP)-PCR revealed that CrebA expression is regulated by CREB-binding protein (CBP), which is sequestered by polyQ proteins. Furthermore, co-overexpression of CrebA and Rac1 synergistically restores the polyQ-induced dendrite pathology. Collectively, our results suggest that GOPs impaired by polyQ proteins contribute to dendrite pathology through the CBP-CrebA-COPII pathway.

Original languageEnglish
Pages (from-to)356-369
Number of pages14
JournalCell Reports
Volume20
Issue number2
DOIs
StatePublished - 11 Jul 2017

Bibliographical note

Funding Information:
We would like to thank Dr. Joshua Bagley (IMBA, Vienna) for helpful discussion and critique on our manuscript. This work was supported by the DGIST R&D and MIREBraiN program, Basic Science Research Program through the Ministry of Science, ICT, and Future Planning of Korea (17-BD-0402, 17-BT-02, and 17-01-HRSS-02), the Development of Platform Technology for Innovative Medical Measurements Program from the Korea Research Institute of Standards and Science (KRISS-2017-GP2017-0020; to S.B.L.), and The Institute for Basic Science (IBS-R013-G1; to D.H.) funded by the Ministry of Science, ICT, and Future Planning of Korea.

Publisher Copyright:
© 2017 The Author(s)

Keywords

  • CBP
  • CREB3L1
  • CrebA
  • Golgi outposts
  • ataxin-3
  • dendrites
  • neurodegeneration
  • nuclear proteotoxicity
  • polyQ

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