# Role of endosulfine-alpha expression and phosphorylation in Parkinson's Disease

> **NIH NIH R03** · PURDUE UNIVERSITY · 2021 · $73,496

## Abstract

Efforts to develop therapies that improve cognitive function in Down syndrome (DS) have so far been
unsuccessful largely because there continue to be gaps in knowledge of molecular mechanisms underlying
neurocircuitry defects in the brains of DS individuals. A hallmark of DS brains is a decrease in glutamatergic
neuronal activity, similar to changes observed in the brains of Alzheimer’s disease (AD) patients. The
phosphoprotein endosulfine-alpha (ENSA) could potentially stimulate neuronal activity in DS brains by
inhibiting ATP-sensitive potassium channels (KATP) channels through its interaction with the SUR1 regulatory
subunit. ENSA phosphorylation at serine 109 (S109) by protein kinase A has been shown to influence the
protein’s interactions with various binding partners and is predicted to favor ENSA-SUR1 binding.
Understanding the impact of ENSA or pS109-ENSA on neuron function in DS is essential in order to validate
ENSA as a therapeutic target in the brains of DS individuals. The long-term goal of this research is to define
molecular mechanisms that contribute to neuronal dysfunction and neurodegeneration in CNS disorders such
as Parkinson’s disease (PD), AD, and DS, with a view towards developing new therapies. The overall objective
in this application is to determine the effects of ENSA expression and S109 phosphorylation on neuronal
activity in DS. The rationale for this research is that its successful completion would provide a strong evidence-
based foundation to justify screening for agents that favor ENSA-mediated KATP inhibition as new therapeutic
candidates for DS. The central hypothesis, formulated on the basis of extensive published data, is that ENSA
down-regulation and a decrease in S109 phosphorylation lead to a reduction in neuronal firing in DS brains.
This hypothesis will be addressed with the following specific aims: (1) Determine the effect of ENSA knockout
on neuron activity in a cellular DS model; and (2) Determine the relative abundance of pS109-ENSA in DS
brains. Aim 1 studies will involve comparing neurons derived from human trisomy-21 iPSCs, with or
without a CRISPR-mediated ENSA gene deletion, in terms of activity monitored using a multi-electrode
array and via confocal microscopy using a fluorescent Ca2+ reporter. A subset of ENSA knockout neurons will
be transduced with lentivirus encoding the non-phosphorylatable and phosphomimetic variants S109A and
S109E. Aim 2 studies will involve characterizing homogenates prepared from DS and control cortical samples
in terms of relative levels of ENSA S109 phosphorylation via quantitative LC-MS/MS, and validating the MS
data via immunoblotting and immunohistochemistry using a new anti-pS109-ENSA antibody. This approach is
innovative because it is focused on new directions related to the role of ENSA in DS. The research is
significant because the new knowledge from this study would set the stage for developing therapeutic
strategies to ameliorate cognitive impairment in DS ...

## Key facts

- **NIH application ID:** 10404860
- **Project number:** 3R03NS108229-01A1S1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** JEAN-CHRISTOPHE ROCHET
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $73,496
- **Award type:** 3
- **Project period:** 2021-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404860

## Citation

> US National Institutes of Health, RePORTER application 10404860, Role of endosulfine-alpha expression and phosphorylation in Parkinson's Disease (3R03NS108229-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10404860. Licensed CC0.

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