# Targeting alpha-synuclein after cerebral ischemia as a function of sex and age

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $329,123

## Abstract

Alpha-synuclein (α-Syn) is one of the most abundant proteins in the CNS that is known to be a major player in
the neurodegeneration observed in Parkinson’s disease. We show that stroke (transient focal ischemia)
upregulates α-Syn protein expression and nuclear translocation in neurons of adult rodents and humans. We
further show that knockdown or knockout of α-Syn significantly decreases the infarction and promotes better
neurological recovery in rodents subjected to focal ischemia. Based on these exciting new leads, in this
proposal we wish to test the therapeutic potential of targeting α-Syn in post-stroke brain by following the criteria
set by the Stroke Treatment Academic Industry Roundtable (STAIR) consortium. Aim 1 is to evaluate the
window of therapeutic opportunity, effect of sex, age, route of administration and toxicity of α-Syn siRNA
therapy following focal ischemia in rodents.
We further observed that a microRNA called miR-7a potently targets α-Syn. Importantly miR-7a showed an
inverse relation to α-Syn (miR-7a levels were down-regulated while α-Syn levels were upregulated after
stroke). Hence, we will test the efficacy of replenishing miR-7a in the post-stroke brain to repress α-Syn and
thus decrease brain damage. Testing alternate approaches to target a protein gives better opportunities for
future clinical translation. Hence, miR-7a mimic therapy will serve as an alternate approach to α-Syn siRNA
therapy. Aim 2 is to evaluate the window of therapeutic opportunity, effect of sex, age, route of administration,
toxicity and long-term effects of miR-7a mimic after focal ischemia.
The mechanisms that contribute to α-Syn-mediated secondary brain damage after stroke are not well
understood. We demonstrate that α-Syn protein formed in excess in brain during the acute phase after stroke
oligomerizes and forms aggregates with time. We further show that α-Syn promotes brain damage by multiple
pathologic mechanisms including mitochondrial fission. In chronic neurodegeneration, α-Syn is known to act as
an essential scaffolding molecule for the activation of GSK-3β and the subsequent Tau hyperphosphorylation
that leads to activation of Drp1 which promotes mitochondrial fission. In preliminary studies we observed
increased phosphorylation of GSK-3β, Tau and Drp1. In Aim 3, we will test if α-Syn promotes post-ischemic
mitochondrial fission and brain damage by involving GSK-3β and Tau.
The long-term goal of these studies is to evaluate if targeting α-Syn is a viable option for stroke therapy in both
males and females and at different ages.

## Key facts

- **NIH application ID:** 9891108
- **Project number:** 5R01NS101960-04
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Raghu VEMUGANTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,123
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891108

## Citation

> US National Institutes of Health, RePORTER application 9891108, Targeting alpha-synuclein after cerebral ischemia as a function of sex and age (5R01NS101960-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891108. Licensed CC0.

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