# Determining the critical time window of action of Parkinson mutant alpha synuclein expression in mice

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $245,625

## Abstract

Parkinson Disease (PD) is a debilitating neurodegenerative disease, leading to progressive motor
and cognitive dysfunction that affects 1% of the population over the age of 60. Although often considered a late
onset disease, several lines of evidence suggest that disease onset occurs decades before motor symptoms
arise. Prodromal PD symptoms, like intestinal dysmotility, anosmia, sleep disturbances, and depression may
present decades prior to the onset of motor deficits, at which point a patient has lost ≥60% of their dopaminergic
(DA) neurons from the substantia nigra (SN). Therefore, this proposal addresses a pivotal question in the study
of late onset neurological disease. The overarching aim of this proposal is to define the timeline along which PD-
related neurodegeneration begins, versus when it begins to produce quantifiable and potentially irreversible
neurological effects. We will begin addressing this question by determining whether there is a critical time interval
in which a PD causative mutation mediates its pathological effect. Indeed, PD mouse models that constitutively
express disease-causing mutations often yield milder phenotypes than those induced later in life. The
observation of this effect in multiple independent strategies points to the potential for developmental
compensation rather than a technical or experimental phenomenon. Whether expression of PD-causing
mutations mediate their effects in a time dependent manner, remains largely untested. By characterizing this
window of pathological effect, our proposed work has the potential to inform a new wave of research involving
therapeutic strategies and early disease screening.
 We propose to employ a tetracycline (Tet)-inducible model of the human alpha synuclein (SNCA) hA53T
PD mutation, under the control of a DA neuron regulatory sequence (PITX3-IRES2-tTA/tetO-A53T) to study this
question directly. To ensure the biological robustness of addressing this question with this Tet-Off model, we will
first evaluate the latency between administration of the tetracycline analog, doxycycline (Dox), and repression of
SNCA A53T transcript and protein levels, as well as between Dox removal/washout and SNCA A53T de-
repression. Next, to determine whether the pathological effect of mutant SNCA is mediated throughout life or
within a defined time window (e.g., gestation, postnatal, juvenile, or mid-adult life), we will activate expression of
the mutant protein across five time windows: between mid-gestation (embryonic day 15.5) and postnatal day 21
(P21), between E15.5 and postnatal day 60 (P60), between P21 and mid-late adulthood (8-16 mos), between
P60 and mid-late adulthood (8-16 mos), and mid-late adulthood (8-16 mos). These will be compared to controls
expressing the mutant protein from E15.5 onwards and those in which the mutant protein remains inactivated.
We will use well-established assays to evaluate the impact on behavioral, motor, and histological phenotypes.
Our proposal will...

## Key facts

- **NIH application ID:** 10887670
- **Project number:** 1R21NS126731-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Hanseok Ko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $245,625
- **Award type:** 1
- **Project period:** 2024-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887670

## Citation

> US National Institutes of Health, RePORTER application 10887670, Determining the critical time window of action of Parkinson mutant alpha synuclein expression in mice (1R21NS126731-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10887670. Licensed CC0.

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