# NDST3‐Induced Epigenetic Reprogramming Reverses Neurodegeneration in Parkinson's Disease

## TL;DR

NDST3 can reverse Parkinson's disease by reprogramming neurons to restore function and halt degeneration.

## Contribution

NDST3 is shown to reverse neurodegeneration through epigenetic reprogramming in Parkinson's disease.

## Key findings

- NDST3 administration revitalizes dopaminergic neurons and restores motor function in PD models.
- NDST3 reactivates pathways linked to neuronal survival and synaptic integrity.
- Epigenetic reprogramming by NDST3 steers cells toward a resilient phenotype in key motor circuits.

## Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons (DN) in the substantia nigra and disruption of cellular maintenance. Here, we demonstrate that NDST3‐mediated epigenetic reprogramming halts neuronal degeneration and restores motor function in an animal model of PD. Following NDST3 administration, the DN and its associated circuits in the substantia nigra and striatum showed marked revitalization, accompanied by a considerable alleviation of PD‐like motor deficits. Integrative single‐cell and spatial RNA sequencing with CUT&RUN revealed that NDST3‐driven reactivation of pathways is linked to neuronal survival, synaptic integrity, and steering of compromised cells toward a resilient phenotype. By recalibrating the epigenetic landscape, NDST3 promotes cellular maintenance and functional recovery in key motor circuits. These findings highlight NDST3's therapeutic potential as an epigenetic modulator of PD. These findings provide insights into the mechanisms underlying neuronal revitalization and highlight the potential of NDST3 as a novel agent for restoring brain function in neurodegenerative conditions.

NDST3‐mediated epigenetic reprogramming revitalizes neuronal circuits in the substantia nigra and striatum to halt dopaminergic neuron degeneration and restore motor function in Parkinson's disease models. This strategy promotes neuronal maintenance and functional recovery, highlighting NDST3's therapeutic potential in neurodegenerative disorders.