pr500329w_si_001.pdf (393.63 kB)
Proteomics Analysis of Amyloid and Nonamyloid Prion Disease Phenotypes Reveals Both Common and Divergent Mechanisms of Neuropathogenesis
journal contribution
posted on 2015-12-17, 05:41 authored by Roger A. Moore, Dan E. Sturdevant, Bruce Chesebro, Suzette A. PriolaPrion
diseases are a heterogeneous group of neurodegenerative disorders
affecting various mammals including humans. Prion diseases are characterized
by a misfolding of the host-encoded prion protein (PrPC) into a pathological isoform termed PrPSc. In wild-type
mice, PrPC is attached to the plasma membrane by a glycosylphosphatidylinositol
(GPI) anchor and PrPSc typically accumulates in diffuse
nonamyloid deposits with gray matter spongiosis. By contrast, when
mice lacking the GPI anchor are infected with the same prion inoculum,
PrPSc accumulates in dense perivascular amyloid plaques
with little or no gray matter spongiosis. In order to evaluate whether
different host biochemical pathways were implicated in these two phenotypically
distinct prion disease models, we utilized a proteomics approach.
In both models, infected mice displayed evidence of a neuroinflammatory
response and complement activation. Proteins involved in cell death
and calcium homeostasis were also identified in both phenotypes. However,
mitochondrial pathways of apoptosis were implicated only in the nonamyloid
form, whereas metal binding and synaptic vesicle transport were more
disrupted in the amyloid phenotype. Thus, following infection with
a single prion strain, PrPC anchoring to the plasma membrane
correlated not only with the type of PrPSc deposition but
also with unique biochemical pathways associated with pathogenesis.