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

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.

Coiled-coil structure-dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects

“…For example, Richards et al ( 9 ) showed that dendrite defects were associated with perturbations of the Rab11-dependent endosomal recycling system in a Drosophila model of Huntington’s disease. In addition, we previously demonstrated that dendrite defects were associated with perturbed actin cytoskeletal structure and impaired subcellular distribution of Golgi outposts in Drosophila models of SCA type 3 (SCA3), also known as Machado–Joseph disease (MJD) ( 10 , 11 ). Despite these efforts, the molecular mechanism of polyQ protein toxicity and the link to the resulting dendrite pathology remain largely unknown.…”

Mechanisms of protein toxicity in neurodegenerative diseases

“…Transcriptional and epigenetic alterations have been shown to contribute to the broad spectrum of neuronal phenotypes ranging from early neuropathic features to late-stage neuronal cell death in polyQ diseases [ 31 ]. For instance, recent studies showed that polyQ proteins induced early changes to the dendrite morphology through the perturbation of RNA granule formation and transcriptional cascades regulating the ER-to-Golgi (COPII) pathway [ 37 – 39 ]. In the SCA1 mouse model, the translational repressor Capicua was shown to be critically involved [ 40 ], and in HD and DRPLA mouse models, treatment with histone-deacetyltransferase (HDAC) inhibitors (sodium butyrate, 4-phenylbutyric acid sodium salt, and suberoylanilide hydroxamic acid) was shown to ameliorate neurotoxicity [ 41 – 44 ].…”

Basal autophagy is required for promoting dendritic terminal branching in Drosophila sensory neurons

“…The observations that disruption of individual Atg genes only partially suppresses Cut overexpression effects on C-I md neuron dendritic growth and filopodial-like terminal branching and that overexpression of Atg1 alone is insufficient to fully rescue cut loss-of-function dendritic defects in C-III md neurons can be explained in light of recent studies demonstrating that Cut functions via a variety of cellular processes in regulating dendritic development [ 3 ]. Recent neurogenomic studies demonstrate that Cut positively regulates the expression of hundreds of genes in md neurons [ 36 ] and functional studies have implicated molecules involved in cytoskeletal regulation [ 36 , 43 , 57 , 58 ], secretory pathway function [ 23 , 59 ], cell adhesion [ 39 ], and ribosomal regulatory function [ 36 ] as downstream effectors of Cut-mediated dendritic growth and branching, including the formation of dendritic filopodial-like terminal branches characteristic of C-III md neurons. These previous findings, coupled with our current results implicating autophagy, reveal that Cut exerts complex transcriptional effects on a broad spectrum of cellular processes that converge to promote dendritic diversity in md neurons and regulate terminal dendritic branching.…”