# Project 3: Structural basis of amyloid formation and chaperone-mediated turnover

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $355,300

## Abstract

PROJECT SUMMARY
Currently there are no known treatments that slow or prevent Alzheimer’s and other neurodegenerative
diseases, and the molecular mechanisms that underlie the progression of these diseases are poorly
understood. Our broad goal is to address critical problems in macromolecular structure determination of
disease-relevant conformations of Aβ and tau prions and associated protein regulatory complexes in order to
advance mechanistic understanding of prion propagation and guide novel therapeutic approaches. We will
achieve this goal using high-resolution cryo-electron microscopy (cryo-EM) methods and: (1) Develop affinity
capture methods on cryo-EM grids for extracting specific filaments from tissue for structure determination; (2)
Determine cryo-EM structures of Aβ and tau fibril conformations derived from in vitro assembly and mouse
models and compare with those determined from human tissue; and (3) Determine mechanisms and
interactions by the Hsp70 molecular chaperone machinery that regulate prion propagation, ubiquitination, and
clearance. With these goals we will identify the structural basis for amyloid fibrils that develop during disease
and uncover key chaperone regulatory processes critical for quality control and clearance of proteins that form
toxic amyloids.

## Key facts

- **NIH application ID:** 10170177
- **Project number:** 5P01AG002132-40
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Daniel Ryland Southworth
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,300
- **Award type:** 5
- **Project period:** 1997-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170177

## Citation

> US National Institutes of Health, RePORTER application 10170177, Project 3: Structural basis of amyloid formation and chaperone-mediated turnover (5P01AG002132-40). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10170177. Licensed CC0.

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