期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 7, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s40478-019-0857-5
关键词
Axonal transport; Alzheimer's disease; Kinesin-1; Kinesin light chain; Amyloid precursor protein; Calsyntenin-1; Drosophila melanogaster
资金
- Alzheimer's Research UK [ART-PG2011-5, ARUK-PG2014-5, ARUK-PG2017B-3, ARUK-EG2013B-1, ARUK-RF2015-5]
- UK BBSRC [BB/L019299/1]
- UK MRC grant [MR/R022666/1]
- NC3Rs David Sainsburys fellowship
- Academy of Medical Sciences Springboard Award [SBF004/1088]
- van Geest Fellowship in Dementia and Neurodegeneration
- van Geest PhD studentship
- SKT grants [N/N001753/2, NC/T001224/1]
- BBSRC [BB/L019299/1] Funding Source: UKRI
- MRC [MR/R022666/1] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据