# Structural basis and physiological consequences of alpha-Synuclein binding to neurexin 1beta

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $557,301

## Abstract

Project Summary/Abstract
 α-Synuclein is a small, soluble neuronal protein that is the primary component of the Lewy body aggregates
that are the hallmark of Parkinson's disease. While the mechanistic details are not yet well-understood,
emerging evidence suggests that cell-to-cell transmission of toxic forms of α-Synuclein is the basis of disease
propagation. Our lab has recently identified complex N-linked glycans as mediators of cellular internalization of
both monomer and aggregate forms of α-Synuclein bearing an N-terminal acetyl group, a physiological
modification of the protein. We specifically identified the neuronal glycoprotein neurexin 1β as capable of
driving internalization of α-Synuclein in a glycan-dependent manner. The goal of our proposed research is to
characterize the structural basis of α-Synuclein binding to neurexin 1β, the role of both N-terminal acetylation
and glycosylation in conferring specificity in this interaction, and determine the molecular mechanisms resulting
cellular internalization of α-Synuclein following binding neurexin 1β. Our hypothesis is that cell-to-cell
transmission of αS is dependent on interactions with neurexin 1β and that the selectivity in these interactions is
dependent on transient structural changes in α-Synuclein conferred by the N-terminal acetyl group. To
investigate this hypothesis, we have developed three specific aims with the following goals: determine the
structural features of α-Synuclein bound to neurexin 1β, including defining a minimal α-Synuclein construct
required for binding (Aim 1); determine the mechanisms by which binding to neurexin 1β results in cellular
internalization of α-Synuclein (Aim 2); and understand the functional impact of α-Synuclein binding to neurexin
1β (Aim 3). To achieve these goals, we will carry out in vitro coarse grain and high resolution structural
characterization of α-Synuclein:neurexin 1β complexes and use live-cell imaging to quantify internalization of
α-Synuclein and the ability of internalized α-Synuclein to seed aggregation of endogenous α-Synuclein. We
will contrast WT monomer, PD-associated point mutants and fibrillar forms of α-Synuclein. Through this
research we expect to characterize key interactions involved in propagation of α-Synuclein pathology in
Parkinson's disease, as well as to gain insight into the structural features of α-Synuclein:neurexin 1β
complexes. Ultimately, the characterization of α-Synuclein: neurexin 1β interactions carried out through our
studies may provide a new target for Parkinson's disease treatment and serve as the basis identifying novel
small molecule therapeutics.

## Key facts

- **NIH application ID:** 10871686
- **Project number:** 5R01NS120625-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Elizabeth Rhoades
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $557,301
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871686

## Citation

> US National Institutes of Health, RePORTER application 10871686, Structural basis and physiological consequences of alpha-Synuclein binding to neurexin 1beta (5R01NS120625-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871686. Licensed CC0.

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