# Screening for Compounds that Lower Intracellular Alpha-Synuclein Levels

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $129,915

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of this Supplement, as with the parent grant, is to identify agents that reduce the levels and
accumulation of alpha-synuclein (αSyn) that underlies the pathogenesis of Parkinson's disease (PD). The
premise of this Supplement proposal is supported by preliminary data from the parent grant and by numerous
reports including point mutations or duplication/triplication of the SNCA (Synuclein Alpha) gene that results in
αSyn increases leading to autosomal-dominant early-onset PD. The finding that the promoter for the SNCA gene
is hypomethylated in PD resulting in increased expression and that over-expression of the gene is a factor
contributing to onset of PD suggests reducing the levels of αSyn is a promising target for therapeutic intervention.
Furthermore, reduction of αSyn levels using agents such as β2-adrenoreceptor (β2AR) agonists has been
reported to be neuroprotective in both cell line and rodent models. An epidemiological analysis of a Norwegian
population revealed individuals using β2AR agonist, salbutamol for asthma, have a reduced risk of developing
PD. In this Supplement, as part of expansion of the aim 1, we will evaluate the effect of validated hits on αSyn
oligomerization and formation of intracellular aggregates using the bimolecular fluorescence complementation
(BiFC) assay. Such inhibitors could reduce intracellular αSyn levels by downstream effects enhancing αSyn
degradation. The Lewy-related pathology (LRP), primarily comprised of αSyn, is not restricted to PD and has
been found in a subset of autopsied Alzheimer's disease (AD) brains and brains of Dementia with Lewy Bodies
(DLB) patients. Apolipoprotein E4, a risk factor for AD, is also a risk factor for PD and is associated with earlier
onset of PD. A recent study also suggests there is a link between higher levels of αSyn in the CSF and early
stages of development of cognitive decline in AD. In this Supplement as part of expansion of the aim 3 we will
evaluate prioritized hits in iPSC derived neurons for effect on AD biomarkers. Current therapeutics for PD
provide only symptomatic relief, there is an urgent need for the development of disease-modifying compounds
capable of slowing or halting PD progression. To address this need in PD as well as LRP in AD and DLB, in the
parent proposal we are performing high throughput screening (HTS) of the UCLA 200K compound library to
identify hits that lower intracellular αSyn levels; these hits will be validated and prioritized by potency, drug-like
properties, and brain permeability for further analysis. In this Supplement for Aim 1 Expansion, hits identified
from HTS by AlphaLISA that reduce intracellular αSyn in SK-N-MC human neuroepithelioma cells and are
validated in primary and secondary assays in the parent grant would be evaluated in αSyn oligomerization using
the BiFC assay that we will set up during the Supplement proposal. This will enable further elucidation of the
mechanism of action (MoA) of...

## Key facts

- **NIH application ID:** 10524695
- **Project number:** 3R21AG063007-01A1S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Varghese John
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $129,915
- **Award type:** 3
- **Project period:** 2021-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10524695

## Citation

> US National Institutes of Health, RePORTER application 10524695, Screening for Compounds that Lower Intracellular Alpha-Synuclein Levels (3R21AG063007-01A1S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10524695. Licensed CC0.

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