# Mechanisms of Prion Spread

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $339,063

## Abstract

Prion diseases are among the most rapidly progressive neurodegenerative disorders and are
characterized pathologically by extracellular prion aggregates, synaptic damage, neuronal loss,
and severe astrogliosis in the brain and spinal cord. Prion aggregates spread through
neuroanatomically connected brain regions, yet how prions physically spread from cell-to-cell is
poorly understood. In vitro, prion aggregates form on the plasma membrane, in endosomes, and
in multivesicular bodies, and are released in exosomes from chronically infected cells. A major
goal of this application is to determine how intra-cellular vesicular prion trafficking contributes to
inter-cellular prion spread through the central nervous system using in vitro and in vivo model
systems. We have previously employed a broad range of approaches to track structurally
diverse prions from axon terminals to neuronal cell bodies and have determined the biophysical
properties of highly virulent prions that spread into the CNS. We discovered that small,
subfibrillar and fibrillar prions were internalized by neurons through macropinocytosis. However,
only the small, subfibrillar prions spread from extraneural sites into the brain. Thus, aggregate
size underlies prion spread into the CNS. We also determined that post-translational
modifications in the prion protein can alter aggregate packing arrangements and lead to the
emergence of new prion strains. Finally, we found that autophagic clearance pathways were
induced in muscle cells harboring prion aggregates. In this renewal, we aim to determine how
the vesicular trafficking of prions in neurons and glia impacts prion spread through the CNS. In
Specific Aim 1, we will define the physical properties of a prion that govern packaging into
exosomes. In Specific Aim 2, we will identify key regulators of intracellular prion conversion and
clearance in neurons and astrocytes by manipulating vesicular transit pathways. Additionally we
will characterize vesicular regulatory protein expression in prion-infected humans and in mouse
models. In Specific Aim 3, we will determine how cell-specific repression of early and late
stages of vesicular trafficking modifies prion disease progression. These experiments are the
first to probe the contribution of intra-vesicular prion trafficking pathways to prion spread in vivo,
and will help unravel how vesicular transport impacts prion conversion, clearance, and rapid
spread through the brain. The proposed studies are particularly important with the growing
recognition of endosomal and lysosomal dysfunction occurring in Alzheimer’s and other
neurodegenerative diseases, and with potential opportunities arising for therapeutic intervention
in protein aggregate clearance pathways.

## Key facts

- **NIH application ID:** 9910452
- **Project number:** 5R01NS076896-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christina Sigurdson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,063
- **Award type:** 5
- **Project period:** 2012-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910452

## Citation

> US National Institutes of Health, RePORTER application 9910452, Mechanisms of Prion Spread (5R01NS076896-09). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/9910452. Licensed CC0.

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