NR AWDY
AU DeArmond,S.J.; Ishikura,N.; Spilman,P.; Prusiner,S.B.; Huang,E.
TI Activation of notch-1 signaling pathways link PrPsc accumulation with dendritic atrophy of neurons and hyper-reactive astrocytic gliosis
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-13
PT Konferenz-Poster
AB Neurodegeneration in prion diseases proceeds in a stereotypical set of steps beginning with accumulation of PrPsc in synaptic structures. Dendritic atrophy and presynaptic bouton degeneration start 2 wks later. Nerve cell death is a late event occurring at 1 to 3 months. During CNS development, activation of Notch-1 signaling pathways halts growth and development of dendrites and axons whereas other factors, such as ß-catenin, stimulate their growth. We found a close association between PrPsc accumulation in synaptic regions, activation of Notch-1, and dendritic atrophy in CD1 mice inoculated with prions, but no change in beta-catenin (Ishikura et al. PNAS 102:886-891, 2005). Evidence of Notch-1 activation included release of its intracellular transcription factor domain (NICD) and translocation of NICD to neuronal nuclei. We tested whether the increased NICD levels lead to increased expression of repressor Hes genes and regressive changes in neurons. We found significantly increased Hes5 protein in neocortical homogenates during prion disease relative to age-matched controls. In neurons, double-immunolabeling confocal microscopy revealed markedly increased levels of Hes1 and Hes5 (Hes1/5) proteins mostly in nuclei. In reactive astrocytes, virtually all Hes1/5 colocalized with GFAP in the cytosol, with little or none in nuclei. Nevertheless, NICD was elevated in both the cytosol and nuclei of reactive astrocytes, which correlated with progressive increase in GFAP mRNA expression. The latter argues that the embryonic Notch-1-GFAP pathway was activated in astrocytes, accounting in part for the hypergliotic state of prion diseases. Thus we propose that dendritic atrophy in prion diseases is caused at least in part by activation of Notch-1-Hes pathways. In contrast, reactive astrocytic gliosis is driven by activation of the Notch-1-GFAP pathway. Of equal importance, in astrocytes, sequestration of Hes proteins by glial filaments prevents the suppressive effect of the activated Notch-1-Hes pathway, which allows reactive astrocytic gliosis to develop. These results provide a molecular mechanism linking PrPsc formation and accumulation in the brain to the clinically relevant neuropathological changes in prion disease. (NIH support: AG02132, AG10770, and AG02160).
AD S.J. DeArmond: Departments of Pathology, Neurology, Biochemistry and Biophysics, The Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA; N. Ishikura, P. Spilman: Department of Pathology, The Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA; S.B. Prusiner: Departments of Neurology, Biochemistry and Biophysics, The Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA; E. Huang: Department of Pathology, The Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA, and Pathology Service, Veterans Administration Medical Center, San Francisco, CA, USA. E-mail: stephen.dearmond@ucsf.edu
SP englisch
PO Italien