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

Abstract

ABSTRACT 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. image