Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection
Year: 2023
Type: article
Abstract: Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a abundant extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase) from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of neuronal Ndst1- deficient mice, neuronal, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance.
Source: PLoS Pathogens
Authors: Patricia Aguilar-Calvo, Adela Malik, Daniel R. Sandoval, Christopher Barback, Christina D. Orrù, Heidi G. Standke, Olivia R. Thomas, Chrissa A. Dwyer, Donald P. Pizzo, Jaidev Bapat, Katrin Soldau, Ryotaro Ogawa, Mckenzie B. Riley, K. Peter R. Nilsson, Allison Kraus, Byron Caughey, Jeffrey J. Iliff, David R. Vera, Jeffrey D. Esko, Christina J. Sigurdson
Institutions: University of California San Diego, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Case Western Reserve University, University of Alabama at Birmingham, Linköping University, University of Washington, VA Puget Sound Health Care System, VA Northwest Network, University of California, Davis
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,655
Funders: National Science Foundation, Fundación Ramón Areces, Vetenskapsrådet, National Institutes of Health, University of California, San Diego, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, Creutzfeldt-Jakob Disease Foundation
Awards: G1235137611, G1461063360, G1593744141, Molecular basis of prion protein-induced neurodegeneration, G2463923679, G3502782809, Role of heparan sulfate in neural cell vulnerability to prions, G5059537702, G5550687991, G5658006696, Proteophenes - Optoelectronic Materials for Molecular Imaging and Organic Bioelectronics, G651357916, RAPID: Glycan coreceptors for SARS-CoV-2 spike protein, G9000001325, G9000030168, G9000093946, G9000297145
OpenAlex ID: W4387011792