TY - JOUR
T1 - A highly toxic cellular prion protein induces a novel, nonapoptotic form of neuronal death
AU - Christensen, Heather M.
AU - Dikranian, Krikor
AU - Li, Aimin
AU - Baysac, Kathleen C.
AU - Walls, Ken C.
AU - Olney, John W.
AU - Roth, Kevin A.
AU - Harris, David A.
N1 - Funding Information:
Supported by grants from the National Institutes of Health (HD 37100, to J.W.O.; NS035107 and NS057098, to K.A.R.; and NS052526 and NS040975, to D.A.H.). H.M.C. was supported by a predoctoral fellowship (NS04691003) from the National Institutes of Health.
PY - 2010/6
Y1 - 2010/6
N2 - Several different deletions within the N-terminal tail of the prion protein (PrP) induce massive neuronal death when expressed in transgenic mice. This toxicity is dose-dependently suppressed by coexpression of full-length PrP, suggesting that it results from subversion of a normal physiological activity of cellular PrP. We performed a combined biochemical and morphological analysis of Tg(ΔCR) mice, which express PrP carrying a 21-aa deletion (residues 105-125) within a highly conserved region of the protein. Death of cerebellar granule neurons in Tg(ΔCR) mice is not accompanied by activation of either caspase-3 or caspase-8 or by increased levels of the autophagy marker, LC3-II. In electron micrographs, degenerating granule neurons displayed a unique morphology characterized by heterogeneous condensation of the nuclear matrix without formation of discrete chromatin masses typical of neuronal apoptosis. Our data demonstrate that perturbations in PrP functional activity induce a novel, nonapoptotic, nonautophagic form of neuronal death whose morphological features are reminiscent of those associated with excitotoxic stress.
AB - Several different deletions within the N-terminal tail of the prion protein (PrP) induce massive neuronal death when expressed in transgenic mice. This toxicity is dose-dependently suppressed by coexpression of full-length PrP, suggesting that it results from subversion of a normal physiological activity of cellular PrP. We performed a combined biochemical and morphological analysis of Tg(ΔCR) mice, which express PrP carrying a 21-aa deletion (residues 105-125) within a highly conserved region of the protein. Death of cerebellar granule neurons in Tg(ΔCR) mice is not accompanied by activation of either caspase-3 or caspase-8 or by increased levels of the autophagy marker, LC3-II. In electron micrographs, degenerating granule neurons displayed a unique morphology characterized by heterogeneous condensation of the nuclear matrix without formation of discrete chromatin masses typical of neuronal apoptosis. Our data demonstrate that perturbations in PrP functional activity induce a novel, nonapoptotic, nonautophagic form of neuronal death whose morphological features are reminiscent of those associated with excitotoxic stress.
UR - http://www.scopus.com/inward/record.url?scp=77953206169&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2010.091007
DO - 10.2353/ajpath.2010.091007
M3 - Article
C2 - 20472884
AN - SCOPUS:77953206169
SN - 0002-9440
VL - 176
SP - 2695
EP - 2706
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -