NR AWOE
AU Spilman,P.; Ishikura,N.; Prusiner,S.B.; Huang,E.; DeArmond,S.J.
TI PrPsc and nicastrin determine the rate of notch-1 intracellular domain (NICD) formation in prion disease
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions PA-53
PT Konferenz-Poster
AB Activation of Notch-1-Hes repressor pathways link PrPsc accumulation to dendritic atrophy in mice inoculated with prions (Ishikura et al. PNAS 102:886-891, 2005). Activation of Notch-1 involves at least 2 steps: (1) Ligand-directed cleavage of Notch-1's extracellular domain yielding the truncated transmembrane NEXT peptide and (2) binding of the nicastrin component of the gamma-secretase complex to NEXT followed by intramembrane cleavage of NEXT by Presenilin-1 (PS1) releasing its C-terminal intracellular domain NICD. A correlation of 0.94 between neocortical synaptosomal PrPsc and NICD levels suggested PrPsc may be the main factor controlling rate of NICD formation. From 30 to 60 days postinoculation (dpi) the PrPsc and NICD curves were congruent supporting that possibility. However, from 60 to 90 dpi the rate of NICD formation decreased significantly although PrPsc levels continued to increase exponentially. Then from 90 to 130 dpi the rapid rate of NICD formation returned. These data suggest that at least 2 factors control the rate of NICD formation. Of the key components of the secretase complex, only nicastrin was significantly increased above background levels at 90 and 130 dpi to account for the second increase in the rate of NICD formation. This mid-incubation period increase in nicastrin without an increase in its mRNA suggests decreased degradation of nicastrin. Confocal microscopy showed increased nicastrin in association with PrPsc within dystrophic-appearing aggregates of lysosomes that appear in neurons during mid-incubation period. We propose that PrPsc and nicastrin have different but complementary effects on the rate of NICD formation. PrPsc may act as a Notch-1 ligand triggering NEXT formation. From 30 to 60 dpi baseline nicastrin levels capture most of the NEXT peptide for transport to the gamma-secretase complex to release NICD. From 60 to 90 dpi more NEXT is formed as a result of PrPsc's effect on Notch-1 than can be captured by baseline nicastrin levels. From 90 to 130 dpi, accumulation of large amounts of PrPsc in lysosomes significantly depress degradation of nicastrin increasing its level, which then can keep up with the PrPsc-generated NEXT levels and restore the rate of formation of NICD. (NIH support: AG02132, AG10770, and AG02160).
AD P. Spilman, N. Ishikura: Department of Pathology, University of California, San Francisco, CA, USA; S.B. Prusiner: Departments of Neurology, Biochemistry and Biophysics, and The Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA; E. Huang: The Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA and Pathology Service, Veterans Administration Medical Center, San Francisco, CA, USA; S.J. DeArmond: Departments of Pathology, Neurology, The Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA. E-mail: stephen.dearmond@ucsf.edu
SP englisch
PO Italien