# Novel Proteomics Approach to HIV-Associated Neurocognitive Disorder & Drug Abuse

> **NIH NIH DP1** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $443,672

## Abstract

AD-Related Administrative Supplement for DP1 DA041722, “Aberrant protein S-nitrosylation mediates
synaptic and neuronal toxicity in hiPSC-based models of Lewy Body Dementia (LBD)”
SUMMARY
Lewy body dementia (LBD), classified as an Alzheimer’s disease (AD)-related dementia, represents the
second most common form of neurodegenerative disease after AD in patients above 65 years of age. The key
pathological hallmark of LBD entails accumulation of a-synuclein (αSyn) inclusions, although amyloid-β (Aβ)
and tau pathologies are also typical, suggesting that there are common pathways contributing to dementia in
both LBD and AD. In fact, in LBD and AD brains, synaptic injury and neuronal damage result, at least in part,
from excessive generation of reactive oxygen and nitrogen species (ROS/RNS) engendered by toxic
subspecies of αSyn and/or Aβ. We were the first group to show that aberrant protein S-nitrosylation (forming
SNO-proteins), via RNS (e.g., nitric oxide [NO]) generation, results in synaptic/neuronal damage. Similar to
our findings in the parent DP1 grant in human postmortem brains from patients with HIV-associated
cognitive disorder with methamphetamine drug abuse (HAND/meth), for this supplemental proposal we
present evidence for aberrantly S-nitrosylated proteins in LBD hiPSC models and LBD human brain.
Hence, this supplemental application relates to the parent DP1 grant; moreover, the new work
complements but is totally distinct from our work on AD human iPSCs and AD brain in a prior
supplement to the parent NIDA DP1 award. As an example, our preliminary data provide evidence that
mitochondrial-related protein S-nitrosylation of PINK1, MEF2C and Drp1 plays a causative role in disease-
related damage in LBD. Specifically, we demonstrate that prevention of these aberrant protein S-nitrosylation
reactions ameliorates the disease process, largely abrogating mitochondrial dysfunction, synaptic damage, and
neuronal loss in both cell-based and animal models manifesting misfolded αSyn. Accordingly, we propose the
following Specific Aim for this Supplemental Application:
Specific Aim 1: To determine the effects of oligomeric αSyn and Aβ on SNO-PINK1/SNO-MEF2C/SNO-
Drp1—mediated synaptic dysfunction and neuronal cell death in hiPSC-derived neuronal culture models of
LBD. We will introduce non-nitrosylatable mutant PINK1, MEF2C, or Drp1 via CRISPR/Cas9 in order to test
whether SNO-PINK1, SNO-MEF2C, and SNO-Drp1 contribute in a causal manner to synaptic injury and
neuronal cell death. Importantly, we will compare the effects of oligomeric αSyn/Aβ on hiPSC-derived cortical
neurons vs. A9 dopaminergic neurons since LBD may preferentially affect cerebrocortex over substantia nigra,
respectively.

## Key facts

- **NIH application ID:** 10097476
- **Project number:** 3DP1DA041722-06S2
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** STUART A LIPTON
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,672
- **Award type:** 3
- **Project period:** 2016-04-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10097476

## Citation

> US National Institutes of Health, RePORTER application 10097476, Novel Proteomics Approach to HIV-Associated Neurocognitive Disorder & Drug Abuse (3DP1DA041722-06S2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10097476. Licensed CC0.

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