Prions hijack tunnelling nanotubes for intercellular spread.
In variant Creutzfeldt-Jakob disease, prions (PrP(Sc)) enter the body with contaminated foodstuffs and can spread from the intestinal entry site to the central nervous system (CNS) by intercellular transfer from the lymphoid system to the peripheral nervous system (PNS). Although several means and different cell types have been proposed to have a role, the mechanism of cell-to-cell spreading remains elusive. Tunnelling nanotubes (TNTs) have been identified between cells, both in vitro and in vivo, and may represent a conserved means of cell-to-cell communication. Here we show that TNTs allow transfer of exogenous and endogenous PrP(Sc) between infected and naive neuronal CAD cells. Significantly, transfer of endogenous PrP(Sc) aggregates was detected exclusively when cells chronically infected with the 139A mouse prion strain were connected to mouse CAD cells by means of TNTs, identifying TNTs as an efficient route for PrP(Sc) spreading in neuronal cells. In addition, we detected the transfer of labelled PrP(Sc) from bone marrow-derived dendritic cells to primary neurons connected through TNTs. Because dendritic cells can interact with peripheral neurons in lymphoid organs, TNT-mediated intercellular transfer would allow neurons to transport prions retrogradely to the CNS. We therefore propose that TNTs are involved in the spreading of PrP(Sc) within neurons in the CNS and from the peripheral site of entry to the PNS by neuroimmune interactions with dendritic cells.
Gousset
Karine
K
Unité de Trafic Membranaire et Pathogénèse, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
Schiff
Edwin
E
Langevin
Christelle
C
Marijanovic
Zrinka
Z
Caputo
Anna
A
Browman
Duncan T
DT
Chenouard
Nicolas
N
de Chaumont
Fabrice
F
Martino
Angelo
A
Enninga
Jost
J
Olivo-Marin
Jean-Christophe
JC
Männel
Daniela
D
Zurzolo
Chiara
C
D000588:Amines / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001921:Brain / Q000473:pathology; D002450:Cell Communication; D002460:Cell Line; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D009068:Movement; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D000588:Amines; D018620:PrPSc Proteins; D011328:Prions; D011993:Recombinant Fusion Proteins; C493330:Red DND-99; D049452:Green Fluorescent Proteins