# Structures and biological activity of alpha-synuclein aggregation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $311,462

## Abstract

Summary
Synucleinopathies are a group of neurodegenerative disorders that have been associated to the misfolded
amyloid protein α-synuclein in brain. The misfolded α-synuclein can aggregate into polymorphic fibrils,
displaying distinct biological activities and contributing differently to the diseases. However, the underlying
mechanisms remain unclear. To address this, we will integrate both structural and functional approaches to
study recombinant wild type, disease-related mutants, and brain-derived α-synuclein fibrils. First, we will use
cryo-Electron Microscopy (cryo-EM), combined with other structural methods, to achieve near-atomic
structures of recombinant full-length fibrils of wild type and disease mutant α-synuclein (Aims 1-2). We will
then go beyond structure determination and utilize cellular assays of seeding and toxicity to explore the
biological activities of both wild type and disease mutant α-synuclein fibrils. By comparing the structures of
these fibrils, we will determine structure elements responsible for their biological activity, and correlate
structural differences to seeding and toxicity for a better understanding of their structure-activity relationship
(Aim 2). Finally, we will determine cryo-EM structures of in vivo α-synuclein fibrils derived from the patient
brains of synucleinopathies. Thus we can assess the pathological relevance of the determined recombinant
fibril structures and relate structural features observed in α-synuclein fibrils to different disease states (Aim 3).
Our integrated approach, connecting structure and biological activity of α-synuclein fibrils of different forms or
sources, will reveal atomic understanding of the underlying mechanisms and provide therapeutic targets
suitable for future drug development that precisely targets α-synuclein aggregation to stop synucleinopathies.

## Key facts

- **NIH application ID:** 10150736
- **Project number:** 5R01AG060149-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Lin Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $311,462
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150736

## Citation

> US National Institutes of Health, RePORTER application 10150736, Structures and biological activity of alpha-synuclein aggregation (5R01AG060149-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10150736. Licensed CC0.

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