Abstract
Damage to axonal transport is an early pathogenic event in Alzheimer’s disease. The amyloid precursor protein (APP) is a key axonal transport cargo since disruption to APP transport promotes amyloidogenic processing of APP. Moreover, altered APP processing itself disrupts axonal transport. The mechanisms that regulate axonal transport of APP are therefore directly relevant to Alzheimer’s disease pathogenesis. APP is transported anterogradely through axons on kinesin-1 motors and one route for this transport involves calsyntenin-1, a type-1 membrane spanning protein that acts as a direct ligand for kinesin-1 light chains (KLCs). Thus, loss of calsyntenin-1 disrupts APP axonal transport and promotes amyloidogenic processing of APP. Phosphorylation of KLC1 on serine-460 has been shown to reduce anterograde axonal transport of calsyntenin-1 by inhibiting the KLC1-calsyntenin-1 interaction. Here we demonstrate that in Alzheimer’s disease frontal cortex, KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased; these changes occur relatively early in the disease process. We also show that a KLC1 serine-460 phosphomimetic mutant inhibits axonal transport of APP in both mammalian neurons in culture and in Drosophila neurons in vivo. Finally, we demonstrate that expression of the KLC1 serine-460 phosphomimetic mutant promotes amyloidogenic processing of APP. Together, these results suggest that increased KLC1 serine-460 phosphorylation contributes to Alzheimer’s disease.
Highlights
Intracellular transport of proteins, organelles and other cargoes is an essential requirement for vertebrate cell function
We show that KLC1 levels are reduced and the relative levels of KLC1 serine-460 phosphorylation are increased in Alzheimer’s disease frontal cortex
The calsyntenin-1-KLC1 interaction is regulated by phosphorylation of KLC1 serine-460; phosphorylation promotes release of calsyntenin-1
Summary
Intracellular transport of proteins, organelles and other cargoes is an essential requirement for vertebrate cell function. Damage to axonal transport is known to contribute to Alzheimer’s disease, Parkinson’s disease and motor neuron diseases [6, 10, 15, 19, 36]. Changes in metabolism of APP are believed to contribute to Alzheimer’s disease; mutations in the APP gene cause some dominant familial forms of Alzheimer’s disease and proteolytic processing of APP generates amyloid-β peptide (Aβ) which is deposited as a pathology in the brains of Alzheimer’s disease patients [59].
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