Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors
Christine Bus, Laimdota Zizmare, Marita Feldkaemper, Sven Geisler, Maria Zarani, Anna Schaedler, Franziska Klose, Jakob Admard, Craig J. Mageean, Giuseppe Arena, Petra Fallier‐Becker, Aslihan Ugun‐Klusek, Klaudia K. Maruszczak, Konstantina Kapolou, Benjamin Schmid, Doron Rapaport, Marius Ueffing, Nicolas Casadei, Rejko Krüger, Thomas Gasser, Daniela M. Vogt Weisenhorn, Philipp J. Kahle, Christoph Trautwein, Christian Johannes Gloeckner, Julia C. Fitzgerald
Abstract
, and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches. We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease.