# Stabilizing native α-synuclein homeostasis to prevent insoluble α-synuclein aggregates

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $386,654

## Abstract

Intraneuronal αS aggregates (Lewy bodies and Lewy neurites) are pathological hallmarks of both familial and
sporadic (‘idiopathic’) PD as well as other ‘synucleinopathies’ including dementia with Lewy bodies, multiple
system atrophy and even Alzheimer’s disease. Disease-modifying drugs for treating human synucleinopathies
do not yet exist. This is due in part to a lack of compelling animal and cellular models that recapitulate the
dynamic transition from physiological to non-physiological αS states. Here we propose both new mouse models
and efficient cellular drug screens based on our novel insights about αS structure.
 The PI recently performed a mutagenesis screen for loss of 60/80/100 kDa putative αS multimers that have
now been observed by several labs as apparent native species. He identified key amino acids whose mutation
lowers αS60/80/100 levels and markedly perturbs cellular αS homeostasis with toxic consequences. Importantly,
the αS variants we propose to study in this grant are basically ‘amplifications’ of the fPD/DLB-causing mutation
E46K in KTKEGV repeat #4. They are made by inserting either 1 or 2 additional E46K-like mutations into flanking
repeats #3 and 5. Unlike single αS fPD point mutations that do not produce comprehensive and robust
phenotypes in cell culture, the proposed ‘amplification’ strategy readily produces key features of pathological αS
‘in the dish’: increased αS insolubility, progressive neurotoxicity and formation of round inclusions. The structural
analogy to E46K will make our findings relevant for modeling & treating synucleinopathies.
 Our extensive preliminary data will be exploited in 3 major aims: 1. Novel αS mouse models that express
inclusion-prone αSE35K+E46K (‘αS2K’) and αSE35K+E46K+E61K (‘αS3K’) variants, plus ‘αSKLK’, another
neurotoxic αS motif-mutant. 2. Neuronal models of the toxic αS variants. Special focus will be the characterization
of the striking αS inclusions that form in neuronal somata and neurites, determining their relationship, if any, to
β-sheet-rich αS Lewy aggregates, and defining the inclusions as toxic or protective for the neuron. 3. Performing
screens for factors (genes but principally small drug-like molecules) that can correct the protein dyshomeostasis
that underlies this inclusion formation and neurotoxicity, with the goal of finding synucleinopathy-modifying drugs.
All 3 Aims are based on detailed and technically enabling preliminary studies. We believe that the new research
proposed herein will help overcome the lack of compelling rodent and cellular models to study early aspects of
intraneuronal disease initiation in the pathogenesis of synucleinopathies. Our models will thus be complementary
to approaches that focus on extracellular, non-cell-autonomous spreading models.
 The PI has a strong background in cell biology, biochemistry and neurodegenerative disease research and will
conduct the work in his new, independent laboratory, in collaboration with experts on αS mous...

## Key facts

- **NIH application ID:** 9967140
- **Project number:** 5R01NS099328-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Ulf Dettmer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,654
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967140

## Citation

> US National Institutes of Health, RePORTER application 9967140, Stabilizing native α-synuclein homeostasis to prevent insoluble α-synuclein aggregates (5R01NS099328-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9967140. Licensed CC0.

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