Fast anterograde transport of herpes simplex virus: role for the amyloid precursor protein of alzheimer's disease.
Anterograde transport of herpes simplex virus (HSV) from its site of synthesis in the neuronal cell body out the neuronal process to the mucosal membrane is crucial for transmission of the virus from one person to another, yet the molecular mechanism is not known. By injecting GFP-labeled HSV into the giant axon of the squid, we reconstitute fast anterograde transport of human HSV and use this as an assay to uncover the underlying molecular mechanism. HSV travels by fast axonal transport at velocities four-fold faster (0.9 microm/sec average, 1.2 microm/sec maximal) than that of mitochondria moving in the same axon (0.2 microm/sec) and ten-fold faster than negatively charged beads (0.08 microm/sec). Transport of HSV utilizes cellular transport mechanisms because it appears to be driven from inside cellular membranes as revealed by negative stain electron microscopy and by the association of TGN46, a component of the cellular secretory pathway, with GFP-labeled viral particles. Finally, we show that amyloid precursor protein (APP), a putative receptor for the microtubule motor, kinesin, is a major component of viral particles, at least as abundant as any viral encoded protein, while another putative motor receptor, JIP 1/2, is not detected. Conventional kinesin is also associated with viral particles. This work links fast anterograde transport of the common pathogen, HSV, with the neurodegenerative Alzheimer's disease. This novel connection should prompt new ideas for treatment and prevention strategies.
Satpute-Krishnan
Prasanna
P
Department of Pathology and Laboratory Medicine, Brown University, Providence, RI 02912, USA.
DeGiorgis
Joseph A
JA
Bearer
Elaine L
EL
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D049832:Decapodiformes; D049452:Green Fluorescent Proteins; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology; D018139:Simplexvirus / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D016547:Kinesins