Neuroprotective Effects of <scp>PEP</scp> ‐1‐ <scp>PGAM5</scp> via the Attenuation of Oxidative Stress and Apoptosis in Parkinson's Disease

Parkinson's disease (PD) is driven by mitochondrial impairment and oxidative stress-induced dopaminergic cell death. Phosphoglycerate mutase 5 (PGAM5) augmented accelerating mitophagy and attenuating neuronal apoptosis. Here, we present a novel cell-penetrating PEP-1-PGAM5 fusion protein designed to suppress oxidative damage and apoptosis. We assessed its transduction efficiency and neuroprotective efficacy in vitro and in vivo. PEP-1-PGAM5 was efficiently transduced into SH-SY5Y cells without cytotoxicity. In MPP⁺-exposed cells, PEP-1-PGAM5 attenuated ROS generation, prevented DNA fragmentation, and restored apoptotic signaling. In PD animal model, PEP-1-PGAM5 crossed the blood-brain barrier, preserved tyrosine hydroxylase-positive neurons, and modulated apoptosis markers. These findings demonstrate that delivery of mitochondrial phosphatase PGAM5 via PEP-1 not only mitigates key PD pathologies but also establishes a versatile platform for delivering therapeutic proteins to the brain. PEP-1-PGAM5 thus represents a promising candidate for PD and other neurodegenerative disorders.