# Determination of the clinical relevance of Parkinson disease-associated intronic enhancer of the alpha-synuclein gene, in a novel mouse deletion model

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $204,688

## Abstract

We will evaluate the biological necessity of an intronic enhancer of SNCA and determine its relevance to
Parkinson disease (PD). SNCA is frequently mutated in familial PD; it encodes alpha-synuclein (α-syn), the
primary constituent of Lewy bodies (LB). LB formation/accumulation is a pathological hallmark of PD and is
driven by protein misfolding promoted by SNCA structural mutation, gene amplification, or genetic/environmental
insults that elevate α-syn levels. Noncoding variants predicted to impact SNCA transcriptional regulatory control
are also risk factors for sporadic PD. We recently identified PD-associated variants in SNCA intron 4. These
variants lie within a dopaminergic (DA) neuron open chromatin region (OCR) that we have shown interacts with
the SNCA promoter and is a cis-regulatory enhancer in catecholaminergic neurons. We predict that this
sequence, and the variants therein, impact SNCA transcriptional control and modulate PD risk.
 Hypothesis - Deletion of the Snca enhancer in mice will reduce Snca transcription in PD-relevant cells with
potential impact on their viability/distribution, and on motor/non-motor PD phenotypes (Aim 1); deletion will
reduce DA neuron vulnerability to PD-relevant insults and ameliorate the onset and severity of disease (Aim2).
 Several highly effective strategies exist to elicit Parkinsonian pathology in mice. Tetracycline (tet)-dependent
expression of PD mutant and wild-type (WT) forms of SNCA in DA neurons result in marked and progressive
loss of ventral midbrain DA neuron populations, consistent with PD pathology. Likewise, intrastriatal injection of
α-syn pre-formed fibrils (PFF) also result in a mouse model that exhibits progressive DA neuronal loss.
Consistent with the known role of Snca levels impacting PD risk and progression, α-syn deficient mice are
protected from PFF-induced neurodegeneration and from tet-dependent expression (via viral vector) of the PD
missense mutant (hA53T) or WT SNCA. α-syn null mice are also protected from the neurotoxic effects of other
PD promoting (and Snca-elevating) insults, like MPTP, 6-OHDA, and LPS. We will test whether cell-dependent
titration of Snca levels, similarly, ameliorates risk and progression in a new mouse model.
 We have engineered mouse lines lacking this enhancer (Snca Enhdel) and provide preliminary evidence that
this sequence impacts Snca transcription. Using established techniques, we propose to assay the effect of Snca
Enhdel on prodromal, behavioral, and motor phenotypes (Aim 1a), as well as on PD-relevant neuron
viability/distribution and microglial activation in the midbrain and olfactory bulb (Aim 1b) via
immunohistochemistry and single molecule fluorescence in situ hybridization. Similarly, we will determine
whether Snca Enhdel reduces onset and progression of prodromal/motor/non-motor disease phenotypes (Aim
2a) and impacts DA neuron vulnerability (Aim 2b) when exposed to PD-relevant insults (intrastriatal injection of
SNCA PFF and adenovi...

## Key facts

- **NIH application ID:** 10828923
- **Project number:** 5R21NS128604-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Hanseok Ko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2023-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828923

## Citation

> US National Institutes of Health, RePORTER application 10828923, Determination of the clinical relevance of Parkinson disease-associated intronic enhancer of the alpha-synuclein gene, in a novel mouse deletion model (5R21NS128604-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10828923. Licensed CC0.

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