Nebula/DSCR1 Upregulation Delays Neurodegeneration and Protects against APP-Induced Axonal Transport Defects by Restoring Calcineurin and GSK-3β Signaling

Abstract

Post-mortem brains from Down syndrome (DS) and Alzheimer's disease (AD) patients show an upregulation of the Down syndrome critical region 1 protein (DSCR1), but its contribution to AD is not known. To gain insights into the role of DSCR1 in AD, we explored the functional interaction between DSCR1 and the amyloid precursor protein (APP), which is known to cause AD when duplicated or upregulated in DS. We find that the Drosophila homolog of DSCR1, Nebula, delays neurodegeneration and ameliorates axonal transport defects caused by APP overexpression. Live-imaging reveals that Nebula facilitates the transport of synaptic proteins and mitochondria affected by APP upregulation. Furthermore, we show that Nebula upregulation protects against axonal transport defects by restoring calcineurin and GSK-3β signaling altered by APP overexpression, thereby preserving cargo-motor interactions. As impaired transport of essential organelles caused by APP perturbation is thought to be an underlying cause of synaptic failure and neurodegeneration in AD, our findings imply that correcting calcineurin and GSK-3β signaling can prevent APP-induced pathologies. Our data further suggest that upregulation of Nebula/DSCR1 is neuroprotective in the presence of APP upregulation and provides evidence for calcineurin inhibition as a novel target for therapeutic intervention in preventing axonal transport impairments associated with AD.

Regulation of Axonal Transport by Protein Kinases

“…AD-associated presenilin 1 mutations and hyperphosphorylated tau have also been shown to induce axonal transport defects through activation of GSK3b [25,96,98]. Correcting fast axonal transport defects by reducing GSK3b activity was found to be beneficial in a Drosophila model of AD [99,100]. Deregulation of Cdk5 is also linked to defects in the slow axonal transport of neurofilaments in AD [77].…”

Axonal Transport Defects in Alzheimer’s Disease

“…Therapeutic interventions can be aimed at the specific phosphotransferase activities relevant to AT deficits. Hence, some studies on AD are beginning to focus on investigating proteasome activities; for example, a few recent studies have examined the way proteasomeassociated protein Nedd8 ultimate buster (NUB1)-induced GSK3β degradation [98,99].…”

Molecular characterization of serine/threonine protein phosphatase of Eimeria tenella

“…Increases in Et STP may also be related to drug efflux from the cell, which decreases effective intracellular drug concentrations. Indeed, a study by Shaw and Chang () showed that PP2B is involved in axonal transport. The results of these studies and the present study demonstrated that upregulation of Et STP may be related to drug resistance.…”