# The role of SNX19 in aging brains at single cell resolution and cerebral organoids

> **NIH NIH K01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $118,557

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) and related dementia are devastating neurodegenerative disorders. Despite intensive
investigations, there remains an urgent need to identify the root cause of AD in order to develop efficacious
treatment regimens. SNX19 plays a role in endolysosomal and autophagy pathways, extensively correlated with
neuronal dysfunction and neurodegenerative diseases. Although genetic and cellular evidence suggest SNX19
contributes to neuropathology, the underlying mechanism remains unknown. Here, we propose to study the
mechanism in aging postmortem brain tissue at the single-cell resolution and model SNX19 in human induced
pluripotent stem cell (hiPSCs) derived brain organoids. Using single molecule in situ hybridization experiments,
SNX19 was found to be highly expressed in neurons, particularly excitatory neurons, compared to glia in human
postmortem brains. Our single-nucleus RNA-seq data further demonstrated that SNX19 gene expression is
significantly associated with neuritic plaques in excitatory neurons in postmortem brains. In Aim 1, we propose
to study the link between SNX19 and AD-related pathologies (i.e., neurofibrillary tangle, cognitive impairment)
across six major cell types. Despite the development of animal and in vitro models for AD, they fail to fully
recapitulate all essential aspects of the disease. Brain organoids developed from hiPSCs provide an ideal
experimental model to delineate underlying AD biology before the onset of symptoms. The application of
CRISPR/Cas9 gene editing in iPSCs offers an unprecedented opportunity to functionally assess the role of
SNX19 in affecting neuronal phenotypes. By using genetically modified organoid models, we aim to take the first
crucial step to define neuronal function and the AD-related pathologies associated with SNX19. Our preliminary
data show that SNX19 knockout can increase synaptic markers’ expression in hiPSC-derived neurons and brain
organoids. Our findings implicate aberrant synaptic processes in the underlying AD pathophysiology. Hence, we
propose to assess the impact of SNX19 on synaptic density using the 3D brain organoid model. Given that
SNX19 regulates the endolysosome system, we will test the hypothesis that autophagy might be activated in
SNX19 depletion lines to clear the accumulation of aggregated proteins. We have also observed reduced calcium
responses in co-cultured astrocytes due to SNX19-null organoids. Intracellular calcium levels and glutamatergic
hypofunction are well-established signaling in AD pathogenesis. Accordingly, we will test the hypothesis that
SNX19 impacts neuronal hyperactivity through the overactivation of synapses. Our work integrates techniques
in imaging and biochemistry with rigorous experimental designs using isogenic-engineered hiPSCs from both
genders, and the differentiation of organoids with defined synaptic characteristics. Our research findings will
provide mechanistic insights into the molecular and ...

## Key facts

- **NIH application ID:** 10984597
- **Project number:** 1K01AG084813-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Liang Ma
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $118,557
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984597

## Citation

> US National Institutes of Health, RePORTER application 10984597, The role of SNX19 in aging brains at single cell resolution and cerebral organoids (1K01AG084813-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10984597. Licensed CC0.

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