H6PD Biallelic Variants Inducing Parkinson’s Disease via Disruption of ER-Mitochondria Contact (IMAGE)
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This figure comprehensively presents the genetic association, cellular mechanism, and in vivo model validation of H6PD biallelic variants in Parkinson’s disease (PD). The human genetics section shows biallelic H6PD variants in PD patients (including family pedigree and sequencing data) and dopamine transporter uptake in the brain via ¹¹C-CFT PET/CT. The cellular mechanism section reveals that H6PD deficiency leads to endoplasmic reticulum (ER) oxidative stress, disruption of ER-mitochondria contacts sites (MAMs), reactive oxygen species (ROS) accumulation, and subsequent inhibition of PINK1-Parkin-mediated mitophagy. The in vivo models’ section, using Drosophila (Zw, H6PD ortholog mutants) and mouse (AAV-mediated H6PD knockdown) models, confirm that H6PD deficiency causes dopaminergic neuron loss, motor dysfunction (in Drosophila), and mitochondrial abnormalities (in mice).
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