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Manipulating PrP Glycan Structure to Understand Toxic Signaling Pathways Driving Prion‐Induced Neurodegeneration
Author(s) -
Callender Julia A.,
Sevillano Alejandro M.,
Soldau Katrin,
Khuu Helen,
Aguilar-Calvo Patricia,
Sigurdson Christina J.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.08717
Subject(s) - neurodegeneration , scrapie , transmissible spongiform encephalopathy , glycan , microbiology and biotechnology , protein aggregation , neurotoxicity , biology , neurite , programmed cell death , chemistry , glycoprotein , prion protein , biochemistry , disease , apoptosis , toxicity , in vitro , medicine , organic chemistry , pathology
Prion proteins cause an infectious and rapidly progressive neurodegenerative disease characterized by an exponential increase in prion aggregates as well as spongiform encephalopathy, dystrophic neurites, and neuronal death. These processes depend on the neuronal expression of prion protein (PrP C ), which exists on the outer leaflet of the cell membrane as a glycosylphosphatidylinositol (GPI)‐anchored glycoprotein containing two variably occupied N‐linked glycosylation sites on its carboxy terminus. Previous work has shown that glycan modifications may impact PrP aggregation and neuronal toxicity. To further investigate the role of glycans in prion‐induced neurotoxicity, we have engineered a new knockin mouse model that expresses PrP with an additional glycan on its amino terminus. This mouse spontaneously develops neurodegeneration characterized by spongiform encephalopathy. In contrast to other murine models of prion disease, this neurodegenerative pathology develops in the absence of PrP aggregates or infectivity, as shown by RT‐QuIC, ThT fluorescence, and inoculation of wild‐type mice with brain homogenates from the knockin mouse. Therefore, this model provides the opportunity to investigate the neurotoxic role of PrP C , uncoupled from its aggregation. We show that although the extra glycan does not affect PrP C expression, stability, or turnover in cells, the brains of mice display alterations in autophagy signaling proteins. We are currently further defining the N‐linked glycans on PrP C , with the goal of understanding how glycans mediate the neurotoxic functions of prion protein. These studies hold relevance not only to diseases of prion aggregation, but also to neurodegenerative diseases characterized by protein aggregation in general, including Alzheimer’s, Parkinson’s, and Huntington’s Disease. Support or Funding Information This work was supported by NIH NS15498 awarded to Christina Sigurdson, and by the National Heart, Lung, and Blood Institute of the National Instituters of Health under K12HL141956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.