Deltex 2 Mediates Oxidative Stress and Neurotoxicity in Freezing of Gait of Parkinson's Disease via the Notch2‐Nrf2 Axis

BACKGROUND: Freezing of gait (FOG) is a disabling symptom of advanced Parkinson's disease (PD) with limited therapeutic options. This study identifies Deltex 2 (DTX2) as a novel molecular driver of FOG and elucidates its mechanism. METHODS: FOG rat models were established by bilateral injections of 6-hydroxydopamine (6-OHDA) into the dorsal striatum and bilateral infusions of immunotoxin 192 IgG-saporin into the basal forebrain regions. Proteomic sequencing was performed to identify differentially expressed proteins in the striatum. In vitro studies employed human dopaminergic-like SH-SY5Y cells differentiated with retinoic acid. Cellular responses were evaluated by assessing cell viability, apoptosis, reactive oxygen species (ROS) levels, dopamine content, and tyrosine hydroxylase (TH) expression. RESULTS: Proteomic profiling revealed significantly elevated DTX2 levels in the striatum of FOG model rats. In vitro, DTX2 knockdown in differentiated SH-SY5Y cells conferred robust protection against 6-OHDA-induced neurotoxicity and oxidative stress, as evidenced by increased cell viability, reduced apoptosis, and diminished ROS accumulation. DTX2 silencing restored dopamine synthesis and TH expression. Mechanistically, DTX2 promoted oxidative stress by ubiquitinating and degrading Notch2, a positive regulator of Nrf2 transcriptional activity. Conversely, DTX2 interference stabilized Notch2, thereby enhancing Nrf2 signaling and antioxidant defense. In vivo, striatal knockdown of DTX2 in FOG rats markedly ameliorated gait abnormalities and improved survival of dopaminergic neurons. CONCLUSION: DTX2 emerges as a key molecular driver of freezing of gait in PD. Pharmacological or genetic suppression of DTX2 stabilizes the Notch2-Nrf2 antioxidant axis, rescuing neurons and restoring motor performance in rodent models. These findings identify DTX2 as a readily druggable target for precision therapy aimed at alleviating FOG and improving mobility in patients with advanced PD.