# Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $359,460

## Abstract

Protein misfolding and aggregation to form fibrils are common features of neurodegenerative diseases,
including Alzheimer's Disease, Parkinson's Disease, and related dementias such as Dementia with Lewy
Bodies and Multiple System Atrophy. Drugs that reverse or block protein aggregation, combined with early
diagnosis, provide the prospect for a cure that preserves the patient's memories. To design such drugs and
diagnostic agents, one must understand the process of aggregation within neurons and propagation to “infect”
new neurons to identify the most relevant targets. In this funding period, we propose to use distance
measurements made with fluorescence and crosslinking probes to drive computational models of the misfolding
and aggregation of the proteins α-synuclein (αS) and tau. We will model not only monomeric αS and tau, but
also aggregated forms that are not amenable to characterization by solid state NMR (ssNMR) or cryo-electron
microscopy (cryo-EM). Our computational models will be used to predict the binding of small molecules in order
to validate their molecular details and establish their potential for use in the design of inhibitors and diagnostic
agents. Our methods can also be used to study different misfolded αS and tau polymorphs, which exhibit
different tendencies to form new fibrils and different levels of cytotoxicity. For example, recent investigations of
αS, the primary aggregator in Parkinson's Disease, have shown that tau fibrils can be seeded by some
conformational forms (“strains”) of αS fibrils, but not others. We will investigate the chemical scale differences in
structure between αS strains and the basis for tau fibril seeding by certain strains. This will shed important
insight on the pathology of Parkinson's Disease, Dementia with Lewy Bodies, and Multiple System Atrophy; it
will also set the stage for investigations of other secondary tau pathologies, such as Aβ-seeded tau aggregates
in Alzheimer's Disease.

## Key facts

- **NIH application ID:** 10133161
- **Project number:** 5R01NS103873-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ernest James Petersson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $359,460
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133161

## Citation

> US National Institutes of Health, RePORTER application 10133161, Studying Aggregation in Neurodegenerative Disease Using Synthetic Proteins (5R01NS103873-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133161. Licensed CC0.

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