# Neurovascular functions of a small RNA Snord118-mediated ribosome biogenesis

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $453,750

## Abstract

PROJECT SUMMARY / ABSTRACT
Dysfunction of neurovascular unit (NVU) contributes to diffuse white matter disorder associated with small-
vessel disease (SVD), which affects approximately 50% of all dementia, including Alzheimer's disease and
Alzheimer's disease-related dementias (AD/ADRD). Ribosomopathies are a group of human disorders caused
by mutations in ribosomal proteins or ribosome biogenesis factors. How dysregulation of a universal ribosome
biogenesis process leads to tissue-specific phenotypes remains poorly understood. The goal of this proposal is
to develop two new genetic mouse models for SVD and use them to determine how NVU cell type(s) are
selectively vulnerable to the disruption of a ubiquitous ribosome biogenesis process. We will focus on
noncoding RNA Snord118, which encodes a ribosome biogenesis factor. Snord118 point mutations in humans
lead to SVD named leukoencephalopathy with calcifications and cysts (LCC), which represents the first purely
neurological disorder in ribosomopathies. We have assembled the following preliminary data: 1) generated two
independent disease point mutation knock-in (KI) mouse models, which display patient-like motor and cognitive
behavioral abnormalities; 2) identified pericyte loss, and microvascular and white matter injury in these
Snord118 KI mouse brains, which reflects the vascular unit impairment without causing lethal hemorrhage; 3)
developed a new crosslinking and sequencing based technology named PARIS to high throughput map RNA
structures and RNA-RNA interactions at single molecule and genome-wide levels with base-pair resolution; 4)
used PARIS and identified Snord118 targets in mouse brains at early developmental stage. Preliminary data
led us to hypothesize that Snord118 mutation-mediated disruption of ribosome biogenesis selectively affects
NVU cells via targeting rRNAs and non-rRNAs leading to LCC-like phenotypes. To test this hypothesis, two
specific aims are proposed. Aim 1 will establish mouse models of LCC and identify how NVU cell(s) are
selectively affected by Snord118 mutations. Aim 2 will use PARIS coupled with KI mice to identify Snord118
targets in vivo and determine Snord118 RNA structure-function relationships. Using our new KI mice and latest
PARIS, this study will generate the first tractable mouse models that do not currently exist for Snord118 LCC,
identify mechanisms of Snord118 action and LCC disease, uncover a previously unknown vulnerability of
specific NVU cells to the disruption of a ubiquitous ribosome biogenesis process, therefore help to reconcile
the neurological phenotype specificity of ribosomopathies with the global requirement of ribosome biogenesis
in all cells.

## Key facts

- **NIH application ID:** 10355240
- **Project number:** 1R21AG075665-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jianfu Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $453,750
- **Award type:** 1
- **Project period:** 2022-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355240

## Citation

> US National Institutes of Health, RePORTER application 10355240, Neurovascular functions of a small RNA Snord118-mediated ribosome biogenesis (1R21AG075665-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10355240. Licensed CC0.

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