Amyloid fibrils of mammalian prion protein induce axonal degeneration in NTERA2-derived terminally differentiated neurons.
Defects in axonal transport and synaptic dysfunctions are associated with early stages of several neurodegenerative diseases including Alzheimer's, Huntington's, Parkinson's, and prion diseases. Here, we tested the effect of full-length mammalian prion protein (rPrP) converted into three conformationally different isoforms to induce pathological changes regarded as early subcellular hallmarks of prion disease. We employed human embryonal teratocarcinoma NTERA2 cells (NT2) that were terminally differentiated into neuronal and glial cells and co-cultured together. We found that rPrP fibrils but not alpha-rPrP or soluble beta-sheet rich oligomers caused degeneration of neuronal processes. Degeneration of processes was accompanied by a collapse of microtubules and aggregation of cytoskeletal proteins, formation of neuritic beads, and a dramatic change in localization of synaptophysin. Our studies demonstrated the utility of NT2 cells as valuable human model system for elucidating subcellular events of prion pathogenesis, and supported the emerging hypothesis that defects in neuronal transport and synaptic abnormalities are early pathological hallmarks associated with prion diseases.
Novitskaya
Vera
V
Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA.
Makarava
Natallia
N
Sylvester
Ian
I
Bronstein
Igor B
IB
Baskakov
Ilia V
IV
D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009457:Neuroglia / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D017096:Prion Diseases / Q000378:metabolism* / Q000503:physiopathology; D011328:Prions / Q000378:metabolism*; D017433:Protein Structure, Secondary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D013724:Teratoma; D014855:Wallerian Degeneration / Q000378:metabolism* / Q000473:pathology
D003598:Cytoskeletal Proteins; D011328:Prions; D011993:Recombinant Fusion Proteins; D016708:Synaptophysin