Loss of Golgi Outposts Contributes to the Polyglutamine-induced Dendritic Pathology in Neurons

Identification: Chung, Chang Geon


Description

Loss of Golgi Outposts Contributes to the Polyglutamine-induced Dendritic Pathology in Neurons
 
Chang Geon Chung1,6, Min Jee Kwon1,6, Keun Hye Jeon1,2,9, Do Young Hyeon3,9, Myeong Hoon Han1, Jeong Hyang Park1, In Jun Cha1, Jae Ho Cho1, Kunhyung Kim1, Sangchul Rho1, Gyu Ree Kim1, Hyobin Jeong1, Jae Won Lee4, TaeSoo Kim5, Keetae Kim1, Kwang Pyo Kim4, Daehee Hwang1,3*, and Sung Bae Lee1*
1DGIST, Daegu 42988, Republic of Korea; 2Samsung Medical Center, Seoul 06351, Republic of Korea; 3POSTECH, Pohang 37673, Republic of Korea; 4Kyung Hee University, Yongin 17104, Republic of Korea; 5Ewha Womans University, Seoul 03760, Republic of Korea
6These authors contributed equally
*Correspondence

Neuronal death, which is a hallmark feature of neurodegenerative diseases, is oftentimes preceded by pathological alterations in the neuronal morphology and function. Specifically, dendrite abnormality has been identified as a common feature of neurodegenerative diseases, but the underlying mechanisms are not precisely defined. Here, we used a Drosophila polyglutamine (polyQ) disease model to investigate the mechanistic underpinnings of dendrite degeneration. Overexpression of nuclear polyQ proteins in Drosophila Class IV da (C4da) neurons decreased the number of Golgi outposts (GOPs), supply of plasma membrane (PM), and length of terminal dendrites. mRNA sequencing revealed that polyQ toxicity down-regulated a significant number of secretory pathway-related genes, including COPII genes previously shown to regulate GOP synthesis. Transcription factor enrichment analysis identified that polyQ toxicity reduces the level of CREB3L1/CrebA, whose overexpression rectified the dysregulation of COPII gene expression, GOP synthesis, and PM supply. Furthermore, co-overexpression of CrebA and Rac1 synergistically restored the length of terminal dendrites. By screening a number of candidate upstream regulators of CrebA, we identified CBP as a positive regulator of both CrebA transcription and GOP synthesis. Finally, we showed that polyQ proteins sequester CBP, thereby interfering with its regulatory role in GOP synthesis. Together, these results suggest that the dendrite pathology in polyQ diseases may be linked to the loss of GOPs, the mechanistic link of which involves the perturbation of the CBP-CrebA-COPII pathway.

 

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