# Exploiting New Fibril Structures to Understand the Biophysical Basis for Oligomerization and Toxicity of Alpha-Synuclein

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $361,018

## Abstract

Abstract
 Research into the molecular basis of Parkinson’s Disease has recently undergone a dramatic shift to focus
on toxic, early stage oligomers of α-Synuclein (aSyn). Understanding this promising new therapeutic target, a
departure from research on insoluble fibrils, now requires biophysical insight about the misfolding of aSyn
monomers and subsequent assembly of these toxic oligomers. These oligomer species are far less understood
than fibrils, and more difficult to study, presenting a pressing challenge to biophysicists.
 The specific overall goal of the proposed work is to identify a subset of amino acid interactions within and
between aSyn monomers that are most important in the assembly and toxicity of oligomers. Several new high-
resolution structures of aSyn fibrils will be used as an exciting starting point to launch detailed investigations into
the structural motifs that are present in the early stages of assembly. Based on strong preliminary results, we
hypothesize that, despite their relative structural disorder, there exist robust, targetable structural motifs in early
stage oligomers that persist through fibrilization. Additionally, a subset of those motifs is essential in determining
toxicity: some promote toxic assemblies while others promote cytoprotective assemblies. High-resolution
structures of early-stage oligomers will likely never be solved. Absent structures, our data will do the next best
thing: it will point to specific motifs and residues that stabilize early-stage oligomers and that should be the focus
of directed targeting campaigns.
 We have established a highly resolved technology (both temporally and spatially), time-resolved FRET, that
allows us to study with great sensitivity the early-stages of aSyn aggregation in the cell. We will support these
cellular observations with rigorous biophysical studies including 19F NMR, two-color TIRF microscopy and
computational modeling. We will also utilize our established small molecule discovery technology in an innovative
way to establish whether there are clear structural differences in oligomeric assemblies of the familial variants of
aSyn, and whether these assemblies vary in differing neuronal cell lines.
 In sum, the proposal will provide the field with a significantly deeper understanding of the biophysical basis
of aSyn oligomerization and will draw new correlations between key amino-acid residues, folding and toxicity.

## Key facts

- **NIH application ID:** 10909161
- **Project number:** 5R01NS117968-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Jonathan N Sachs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $361,018
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909161

## Citation

> US National Institutes of Health, RePORTER application 10909161, Exploiting New Fibril Structures to Understand the Biophysical Basis for Oligomerization and Toxicity of Alpha-Synuclein (5R01NS117968-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10909161. Licensed CC0.

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