# Understanding the Mechanism of Pathological alpha-Synuclein Transmission

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

α-Synucleinopathies are a subset of neurodegenerative diseases, including Parkinson's disease (PD),
dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA) (1), which are characterized by
abnormal accumulation of misfolded α-synuclein (α-syn) protein in neurons or glial cells. Emerging evidence
suggests that the cell-to-cell transmission of pathological α-syn substantially cause neurodegeneration.
However, the molecular mechanism of α-syn transmission is poorly understood. We have identified three
transmembrane proteins that strongly bind with α-syn PFF: (i) lymphocyte activation gene-3 (LAG3), (ii)
amyloid β precursor-like protein 1 (APLP1), and (iii) neurexin 1-β. LAG3 is an essential receptor, mediating
internalization of α-syn PFF; however, substantial α-syn PFF binds to LAG3-/- (knockout) neurons, suggesting
that a unidentified candidate(s) (e.g. APLP1) binds with pathologic α-syn, and facilitate the internalization.
In this proposal, we hypothesize: (i) APLP1 is an essential receptor, that mediates α-syn transmission; (ii)
APLP1-LAG3 complex synergistically mediates α-syn transmission; (iii) depletion of APLP1, LAG3, or APLP1-
LAG3 complex, can reduce α-syn-induced neurodegeneration of α-syn transgenic mice. Accordingly,
experiments are proposed to characterize the roles of APLP1, LAG3 and the AL complex in mediating the
pathogenesis of α-synucleinopathies, in cell-to-cell transmission models and the α-syn transgenic
mouse model. Experiments in two mice models with α-synucleinopathies, will be complemented by studies in
cells and cell-free experiments, thus allowing the deciphering of each spreading step in the interaction of
APLP1, LAG3, or the AL complex with pathologic α-syn. The successful completion of these studies will
greatly enhance our understanding of the molecular mechanisms of α-syn cell-to-cell transmission via
receptors, by: (i) identifying APLP1 as a novel receptor that mediates α-syn spreading, (ii) understanding the
synergistic effect of the AL complex on mediating binding and internalization of α-syn PFF, (iii) providing
essential preliminary evaluation of anti-LAG3 antibody as a potential therapeutic agent against PD and related
α-synucleinopathies, and (iv) understanding the roles of APLP1, LAG3, and the AL complex in mediating
neurodegeneration of α-syn transgenic mice.

## Key facts

- **NIH application ID:** 10445274
- **Project number:** 5R01NS107318-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xiaobo Mao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2019-09-17 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445274

## Citation

> US National Institutes of Health, RePORTER application 10445274, Understanding the Mechanism of Pathological alpha-Synuclein Transmission (5R01NS107318-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10445274. Licensed CC0.

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