# Decoding the BETA-arrestin2-LMBRD2 cascade in ALPHA-synuclein pathogenesis.

> **NIH NIH RF1** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $2,069,215

## Abstract

The defining pathological hallmark of Lewy body diseases (LBDs) is the accumulation of misfolded a-synuclein
(aSyn) aggregates, which are heavily phosphorylated at Ser129 (pS129-aSyn). LBDs comprise an array of often
overlapping conditions, including Dementia with Lewy bodies (DLB), Parkinson’s disease (PD), Parkinson’s
disease dementia (PDD), and PD with AD pathology (PD/AD). aSyn is known to regulate synaptic vesicle (SV)
trafficking, including endocytosis. However, how aSyn regulates the endocytic process is poorly understood. In
the pathological setting, aSyn pathology is transmitted from cell to cell through the secretion, internalization,
seeding, and transport of misfolded and toxic aSyn. Despite much progress in understanding these processes,
mechanisms governing the internalization of misfolded aSyn, an early step in its cell-to-cell transmission, remain
unresolved. Based on preliminary studies, our overarching hypothesis is that the binding of b-arrestin2 (bArr2)
to pS129-aSyn regulates membrane endocytosis and that the LMBRD2-bArr2 complex mediates the
internalization, transmission, and toxicity of pathological aSyn.
Utilizing cellular models and animal models combined with pathological, behavioral, electrophysiological,
biochemical, immunohistochemical, in situ protein-protein interaction, and unbiased proteomics studies, we will
validate, dissect, and elucidate the mechanistic basis of the bArr2-LMBRD2 pathway in the regulation of aSyn
function, accumulation, transmission, and toxicity.

## Key facts

- **NIH application ID:** 10978601
- **Project number:** 1RF1NS134638-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** JungA Alexa Woo
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,069,215
- **Award type:** 1
- **Project period:** 2024-08-06 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978601

## Citation

> US National Institutes of Health, RePORTER application 10978601, Decoding the BETA-arrestin2-LMBRD2 cascade in ALPHA-synuclein pathogenesis. (1RF1NS134638-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10978601. Licensed CC0.

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