Abstract
Golgi defects including Golgi fragmentation are pathological features of Alzheimer’s disease (AD). As a pathogenic factor in AD, amyloid precursor protein (APP) induces Golgi fragmentation in the soma. However, how APP regulates Golgi outposts (GOs) in dendrites remains unclear. Given that APP resides in and affects the movements of GOs, and in particular, reverses the distribution of multi-compartment GOs (mcGOs), we investigated the regulatory mechanism of mcGO movements in the Drosophila larvae. Knockdown experiments showed that the bidirectional mcGO movements were cooperatively controlled by the dynein heavy chain (Dhc) and kinesin heavy chain subunits. Notably, only Dhc mediated APP’s regulation of mcGO movements. Furthermore, by loss-of-function screening, the adaptor protein Sunday driver (Syd) was identified to mediate the APP-induced alteration of the direction of mcGO movements and dendritic defects. Collectively, by elucidating a model of bidirectional mcGO movements, we revealed the mechanism by which APP regulates the direction of mcGO movements. Our study therefore provides new insights into AD pathogenesis.
Highlights
The Golgi apparatus, an organelle with a unique cisternal stacked structure, is responsible for protein trafficking, sorting, and processing
Neither dynein heavy chain (Dhc) RNAi nor kinesin heavy chain (Khc) RNAi affected the displacement of the multi-compartment GOs (mcGOs) or single-compartment GOs (scGOs) movements (Figures 2F,G). These results suggest a model for the bidirectional movements of mcGOs: the anterograde and retrograde movements of mcGOs are driven by Dhc and Khc, respectively, and the cooperation of Dhc and Khc maintains the equilibrium of the direction of the mcGO movements
The motility of Golgi outposts (GOs) and the displacements of mcGO movements were not recovered, nor were the characteristics of scGO movements (Figures 4C,F–H and Supplementary Figures 3C–E). These results suggest that the amyloid precursor protein (APP)-induced alteration of the direction of mcGO movements is mediated by Sunday driver (Syd), not Lva and NudE, both Lva and NudE are involved in the regulation of the direction of mcGO movements
Summary
The Golgi apparatus, an organelle with a unique cisternal stacked structure, is responsible for protein trafficking, sorting, and processing. Abnormalities of protein glycosylation have been reported in AD brain tissues, such as an enhancement of glycosylation of the Tyr residue of β-amyloid (Aβ) peptides (Halim et al, 2011) and a decrease of neural sialyltransferase activity (Maguire and Breen, 1995). These results suggest that defects in the Golgi apparatus are pathological features of AD. Previous studies have suggested that defects in the Golgi apparatus are induced by the amyloid precursor protein (APP). Studies have shown that overexpressing APP in neurons leads to Golgi fragmentation, accompanied by swollen
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