# Towards Understanding the Initiating Role of Truncated Alpha-Synuclein in Neurodegeneration

> **NIH NIH F30** · UNIVERSITY OF FLORIDA · 2021 · $40,225

## Abstract

Project Summary/Abstract: Dementia afflicts 47 million individuals worldwide and has an economic impact of
more than $800 billion; neurodegenerative diseases for which no disease modifying therapies exist are the
most common etiology. α-synuclein (αS) aggregates into toxic fibrils in multiple neurodegenerative diseases
where the fibrils form characteristic inclusions implicated in disease progression. Mechanisms through which
initial αS fibrils form is unclear, and yet halting their appearance is key to preventing disease. Carboxy-terminal
truncation (C-truncation) of αS may be crucial in disease pathogenesis, as it has been repeatedly shown in-
vitro that C-truncated αS spontaneously assembles into fibrils more readily than full-length αS. Proteolytic
formation of these truncated species, possibly promoted by aging associated lysosomal impairment, may be
key to initial pathology formation in disease. Additionally, C-truncated αS is increased in disease suggesting a
pathologic role, where 15-20% of αS in inclusions is truncated. Therefore, The Aims of this project are to
characterize naturally formed C-truncated species of αS for their ability to aggregate into pathologic fibrils and
stimulate synergistic formation of αS and tau pathology in-vivo.
Specific Aim one: Investigate the propensity of physiologic C-terminally truncated αS to pathologically
aggregate in-vitro and in cellular models of synucleinopathy and tauopathy. Herein, I will characterize
the aggregation propensity of naturally formed C-truncated αS both in-vitro and in-vivo using well characterized
models. My working hypothesis is that truncated forms of αS will aggregate readily and synergistically induce
full-length αS and tau fibril formation. These results will elucidate molecular mechanisms of aggregation and
set the stage for further in-vivo work.
Specific Aim two: Determine the ability of physiologic C-terminally truncated αS to initiate pathology in
mouse models of synucleinopathy and tauopathy utilizing cerebral fibril injection and recombinant
adeno associated virus (rAAV). Viral overexpression of familial aggregation prone αS mutants in mice results
in neurodegenerative features used to model disease. Additionally, injection of preformed αS fibrils has been
found to hasten progression of the disease in transgenic animals. My working hypothesis is that injection of
truncated αS fibrils, and conversely rAAV overexpression of truncated αS in mice will initiate αS and tau
pathology. These experiments will uncover pathogenic roles for αS truncation in neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10176335
- **Project number:** 5F30AG063446-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Zachary A Sorrentino
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $40,225
- **Award type:** 5
- **Project period:** 2019-05-16 → 2022-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176335

## Citation

> US National Institutes of Health, RePORTER application 10176335, Towards Understanding the Initiating Role of Truncated Alpha-Synuclein in Neurodegeneration (5F30AG063446-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10176335. Licensed CC0.

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