# Mechanistic insights into neurodegeneration in Huntington's disease using patient-derived neurons through direct conversion of fibroblasts

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $333,594

## Abstract

Huntington’s disease (HD) is an inherited adult-onset neurodegenerative disorder caused by an abnormal
expansion of CAG codons in the huntingtin (HTT) gene. HD is characterized by the aggregation of mutant HTT
(mHTT) protein and selective degeneration of striatal medium spiny neurons (MSNs). Modeling HD using
patient-derived neurons has been challenging mainly due to the lack of experimental approaches to obtain
adult neurons from HD patients. Our previous work demonstrated that human MSNs could be generated with
high efficiency and specificity from adult skin fibroblasts through direct cell fate conversion (reprogramming)
using microRNAs and transcription factors. Importantly, the converted human MSNs resembled the neurons of
human adults, an important feature for modeling late-onset diseases. However, the utility of directly converted
MSNs as a cellular model of adult-onset HD remained to be determined. Recently, our preliminary work
demonstrated that MSNs could be generated from directly converting fibroblasts of HD patients (HD-MSNs),
and the resulting HD-MSNs manifested key hallmarks of HD pathology such as mHTT aggregates, DNA
damage, and spontaneous cell death in culture. In the current grant, we propose to use HD-MSNs as a cellular
model of HD and define genetic factors that alleviate the neuronal death of HD-MSNs. In Aim 1, we focus on
SP9, a transcription factor that we found to be significantly downregulated in HD-MSNs in comparison to
control MSNs from healthy individuals (Ctrl-MSNs). Interestingly, SP9 has been reported to be required for the
maintenance and survival of MSNs, and we discovered that enforcing SP9 expression in HD-MSNs protected
the cells from spontaneous cell death. To define the neuroprotective role of SP9 in HD-MSNs, we will identify
direct target genes of SP9 and reveal genes integral to SP9’s function to promote HD-MSN survival. In Aim 2,
we will investigate the function a primate-specific microRNA, miR-663b as a neuroprotective miRNA in HD-
MSNs. Our preliminary work indicated that miR-663b protected MSNs from oxidative stress-induced
neurodegeneration. Given the link between oxidative cellular stress and neurodegeneration in HD-MSNs, we
will test if increasing the miR-663b level in HD-MSNs would confer a neuroprotection and identify direct target
genes of miR-663b to delineate the function of miR-663b in HD-MSNs. In Aim 3, we will identify genetic
pathways responsible for differential vulnerability to neuronal death between MSNs at different stages of
disease progression. We found that HD-MSNs generated from fibroblasts sampled before the onset of clinical
symptoms (pre-HD-MSNs) displayed significantly lower degrees of DNA damage and cell death in comparison
to HD-MSNs derived after the onset of clinical symptoms. We will conduct transcriptome analysis to identify
differentially expressed genes between pre-HD-MSNs and symptomatic HD-MSNs and identify differentially
expressed genes responsible for the differentia...

## Key facts

- **NIH application ID:** 10439654
- **Project number:** 5R01NS107488-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Andrew Yoo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $333,594
- **Award type:** 5
- **Project period:** 2018-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439654

## Citation

> US National Institutes of Health, RePORTER application 10439654, Mechanistic insights into neurodegeneration in Huntington's disease using patient-derived neurons through direct conversion of fibroblasts (5R01NS107488-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10439654. Licensed CC0.

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