# Biologically Novel Mouse Models of PD with Progressive Synucleinopathy and Early-Onset Tremor and Motor Deficits Responsive to L-DOPA

> **NIH NIH RF1** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $1,344,552

## Abstract

Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) produce profound motor and cognitive impairment
associated with aggregation of α-synuclein (αS). Female sex is commonly reported to delay the age of onset and to
produce milder phenotypes, but the reasons are unknown. Accumulation of αS is increasingly implicated in familial
and sporadic forms of these synucleinopathies. Our lab has discovered that female sex preserved a part of
physiologically folded, aggregate-resistant tetrameric αS in PD-type mice, supporting published evidence for the
existence of normal multimeric αS forms in healthy brain. During the first grant period, we have analyzed female sex
and elevation of brain estradiol (by the estradiol prodrug DHED) and showed it can normalize the αS tetramer-
monomer ratio and decrease early LB-type aggregates. Given this progress, we now wish to extend this novel
hypothesis to answer certain key questions about protective estrogen pathways that could be used as disease
modifying treatments. Our proposed new experiments will be enabled by our early-onset, progressive mouse models
in which the E46K-like tetramer abrogating αS mutation (3K) caused sex dimorphism early in the PD-type
neuropathology development. In aim 1, we will determine the age- and sex dependencies of αS pathological
aggregation for WT, 1K and 3K in premature and mature mice. The studies will be controlled in mice with depleted
estrogen. In aim 2, we will investigate the role of extranuclear and synaptic estrogen receptor on the temporal
relationship between changes in synaptic function (electrophysiological studies) and alterations in αS pathologic
aggregation (histopathology and biochemical studies) in genetic model mice with membrane-only estrogen receptor
alpha. We will further examine the effectiveness of a novel therapy that increases palmitoylation (using a small
molecule inhibitor for acyl-protein thioesterase 1) and thereby the level of synaptic estrogen receptors. In aim 3, we
will determine, whether the shared αS tetramer-abrogation by PD risk factors (GBA1-L444P, GBA1-E326K) known
for pathologic excess of soluble wildtype αS monomer accumulation and that produces more severity by male sex,
are also responsive to DHED treatment. We will compare these with our novel familial G51D-and amplified (3D) mice
with excess soluble mutant αS. The results of these studies will be far reaching as they will provide the foundation to
understanding mechanisms through which estrogen prevents αS dyshomeostasis in the brain of robust PD-type mice
in vivo, to improve and create neuroprotective treatments in PD, DLB and Gaucher’s PD.

## Key facts

- **NIH application ID:** 10880982
- **Project number:** 2RF1NS109510-06
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Silke Nuber
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,344,552
- **Award type:** 2
- **Project period:** 2019-05-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880982

## Citation

> US National Institutes of Health, RePORTER application 10880982, Biologically Novel Mouse Models of PD with Progressive Synucleinopathy and Early-Onset Tremor and Motor Deficits Responsive to L-DOPA (2RF1NS109510-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10880982. Licensed CC0.

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