Michael Pacold

V happy to share my work in @RJDLab @CRI_UTSW from past 2 yr! In equal collab with Tony Rodrigues, @dwendscheck, Jorge Azevedo’s lab, @warscheidlab, we have discovered PEX39, the first human peroxisomal biogenesis protein (peroxin/PEX) found in > 20 yr! biorxiv.org/content/10.110…🧵

Just published: nature.com/articles/s4158… Coenzyme Q10 (CoQ10) is critical for mitochondrial function and for controlling reactive oxygen species damage to biological membranes. Because CoQ10 is poorly bioavailable, new approaches are needed to promote CoQ10 synthesis. In our latest paper @Nature, we use CoQ10 headgroup intermediates to restore CoQ10 synthesis in mouse models of HPDL encephalopathy, a rare pediatric neurodevelopmental disease driven by loss of CoQ10 headgroup synthesis. We also use CoQ10 headgroup intermediates to modify the course of this same disease in a patient. Primary CoQ10 deficiencies are rare mitochondrial disorders caused by loss of function of the enzymes that make CoQ10. The neurological symptoms of these diseases respond poorly to CoQ10, likely due to poor bioavailability of this molecule. The newest primary CoQ10 deficiency is HPDL encephalopathy, which is due to loss-of-function variants in the enzyme 4-hydroxyphenylpyruvate dioxygenase-like (HPDL). A few years ago, we discovered that HPDL carries out the first committed step of the mammalian CoQ10 headgroup synthesis pathway, in a study led by Robert Banh @BanhLab: nature.com/articles/s4158… We found that the enzyme HPDL makes 4-hydroxymandelate (4-HMA), the first committed precursor of 4-hydroxybenzoate (4-HB), which generates the CoQ10 headgroup. Patients with HPDL encephalopathy develop spastic paresis, and in severe cases, seizures, neurodevelopmental delay, and death. Mice lacking Hpdl recapitulate these symptoms and die by 15 days after birth. We find that treatment of Hpdl-/- mice with 4-HMA or 4-HB significantly improves the survival of mice from days to years. We treated a single patient with loss-of-function HPDL variants with 4-HB, with dramatic improvement in his symptoms. Thanks to co-authors including Robert Banh @BanhLab and Sota Kuno @kuno_sota, editors George Caputa @curiousdrgeorge and Victoria Aranda @mvicaracal, and reviewers including @RutterLab and everyone at @NYULangone @nyugrossman who made this work possible! Many thanks to our collaborators, Roy Sillitoe @BCMHouston / @TexasChildrens and Alex Joyner @MSKCancerCenter. Grateful for funding from @DamonRunyon @PershingSqFdn @psscra @MindPrize @AmericanCancer @HarringtonDI_UH @OHRareDisease @NIH.