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

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): 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, TaeSoo Kim, Keetae Kim, Kwang Pyo Kim, Michael D. Ehlers, Daehee Hwang, Sung Bae Lee
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.

Graphical abstract

Teaser

Chung et al. show that polyQ toxicity induces dendritic pathology involving loss of Golgi outposts (GOPs) in neurons. Genomic analysis reveals that polyQ inhibits expression of genes in the COPII pathway and GOP synthesis by blocking CBP and downregulating CREB3L1/CrebA expression. Enhancing CrebA restores COPII gene expression and GOP synthesis.


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