# Define molecular events driving selective neuronal death in multiple neurodegenerative diseases by snRNA-seq

> **NIH NIH R03** · WASHINGTON UNIVERSITY · 2021 · $157,500

## Abstract

Project Summary
Despite decades of research, currently the mechanisms of neurodegeneration in Alzheimer’s
disease (AD) and Parkinson Disease (PD) remain controversial and there are no therapies can
prevent, slow, or halt disease progression. Neurodegenerative diseases have two fundamental
general characteristics. 1) The pathology associated with the disease only affects particular
neurons (‘selective neuronal vulnerability’); 2) The pathology worsens with time and impacts more
regions in a stereotypical and predictable fashion. The discovery of key pathways that regulate
this differential susceptibility of neurons to degeneration holds great potential for the discovery of
novel drug targets and the development of promising neuroprotective treatment strategies.
However, the mechanisms underlying selective neuronal and regional vulnerability have been
difficult to dissect because of our limited ability to distinguish different neuronal subpopulations.
Loss of dopaminergic neurons in the SN is a hallmark of PD which underlies the parkinsonian
motor symptoms such as rigidity and tremor. Neuronal loss also occurs in the SN of AD [8, 9],
however, often without co-occurring parkinsonian motor symptoms. Dopaminergic neurons within
the SN are highly heterogeneous [10] and the loss of the dopaminergic neurons in PD is
heterogeneous across different axes [11-14]. It is unclear whether the same population of neurons
were lost in AD and PD and whether the mechanisms of neuronal loss are shared between the
two diseases. Neuroinflammation - activation of the neuroimmune cells (e.g. microglia) into
proinflammatory states - are shared pathological contributors in AD and PD. However, the
molecular identity of different microglia subpopulations and the role of neuroinflammation in the
selective neuronal death remain unclear. Therefore, we propose to use single nucleus RNA-seq
(snRNA-seq), an unbiased approach to identify and characterize distinct cell populations in
tissues, to dissect the mechanisms underlying selective neuronal death. Specifically, our specific
aims are: Aim 1: Characterize and validate cellular heterogeneity, cellular and
transcriptomic changes of neuron and microglia from the SN brain tissues of AD, PD
patients and age-matched controls. Aim 2: Dissect the mechanisms of cell composition
and transcriptome dysregulation in AD and PD. Our study will provide 1) molecular markers
and tools for targeted neuronal and microglia subpopulation isolation and manipulation; 2) better
understanding of the dynamic change of different neuronal and microglia subpopulation, their
transcriptomic changes and the putative regulatory mechanisms in AD and PD; 3) high-
confidence new candidate genes and pathways as targets to develop effective immunotherapies
or neuroprotective strategies.

## Key facts

- **NIH application ID:** 10109536
- **Project number:** 1R03AG070474-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jinbin Xu
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $157,500
- **Award type:** 1
- **Project period:** 2021-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109536

## Citation

> US National Institutes of Health, RePORTER application 10109536, Define molecular events driving selective neuronal death in multiple neurodegenerative diseases by snRNA-seq (1R03AG070474-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10109536. Licensed CC0.

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