Downregulation of ATP6V1A Involved in Alzheimer’s Disease via Synaptic Vesicle Cycle, Phagosome, and Oxidative Phosphorylation

Objective. The objective of this study was to investigate the potential molecular mechanisms of ATPase H+ transporting V1 subunit A (ATP6V1A) underlying Alzheimer’s disease (AD). Methods. Microarray expression data of human temporal cortex samples from the GSE118553 dataset were profiled to screen for differentially expressed genes (DEGs) between AD/control and ATP6V1A-low/high groups. Correlations of coexpression modules with AD and ATP6V1A were assessed by weight gene correlation network analysis (WGCNA). DEGs strongly interacting with ATP6V1A were extracted to construct global regulatory network. Further cross-talking pathways of ATP6V1A were identified by functional enrichment analysis. Diagnostic performance of ATP6V1A in AD prediction was evaluated using area under the curve (AUC) analysis. Results. The mean expression of ATP6V1A was significantly downregulated in AD compared with nondementia controls. A total of 1,364 DEGs were overlapped from AD/control and ATP6V1A-low/high groups. Based on these DEGs, four coexpression modules were predicted by WGCNA. The blue, brown, and turquoise modules were significantly correlated with AD and low ATP6V1A, whose DEGs were enriched in phagosome, oxidative phosphorylation, synaptic vesicle cycle, focal adhesion, and gamma-aminobutyric acidergic (GABAergic) synapse. Global regulatory network was constructed to identify the cross-talking pathways of ATP6V1A, such as synaptic vesicle cycle, phagosome, and oxidative phosphorylation. According to the AUC value of 74.2%, low ATP6V1A expression accurately predicted the occurrence of AD. Conclusions. Our findings highlighted the pleiotropic roles of low ATP6V1A in AD pathogenesis, possibly mediated by synaptic vesicle cycle, phagosome, and oxidative phosphorylation.

Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9

SummaryAutophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated and increases in response to neuronal activity. The mechanisms that couple autophagosome biogenesis to synaptic activity remain unknown. In this study we determine that trafficking of ATG-9, the only transmembrane protein in the core autophagy pathway, links the synaptic vesicle cycle with autophagy. ATG-9 positive vesicles in C. elegans are generated from the trans-Golgi network via AP3-dependent budding, and delivered to presynaptic sites. At presynaptic sites, ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt endocytosis, including one associated with Parkinson’s disease, result in abnormal ATG-9 accumulation at clathrin-rich synaptic foci and defects in activity-dependent presynaptic autophagy. Our findings uncover regulated key steps of ATG-9 trafficking at presynaptic sites, and provide evidence that ATG-9 exo-endocytosis couples autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle.HighlightsIn C. elegans, ATG-9 is delivered to presynaptic sites in vesicles generated from the trans-Golgi network via AP-3-dependent buddingATG-9 vesicles undergo activity-dependent exo-endocytosis at presynaptic sitesMutations in endocytic proteins, including a mutation associated with Parkinson’s disease, result in abnormal ATG-9 accumulation at clathrin-rich fociAbnormal accumulation of ATG-9 at clathrin-rich foci is associated with defects in activity-dependent presynaptic autophagy