A novel function of glyoxalase domain containing protein 4 (GLOD4) is associated with neuron dysfunction and neurodegeneration

Tyrosine nitration alters the structure, function, and/or cellular localization of proteins1,2 and is implicated in the pathology of multiple diseases1-3. Although protein nitration is assumed to proceed via nonspecific chemical mechanisms, it is highly selective, suggesting the possibility of enzymatic catalysis. Here, we showed that glyoxalase domain-containing protein 4 (GLOD4), a previously uncharacterized protein, is an enzyme that catalyzes selective protein nitration. A primary in vivo target for GLOD4-mediated nitration is alpha-synuclein (α-syn), which is central to the development of Parkinson’s disease (PD) and related disorders. GLOD-dependent tyrosine nitration of alpha synuclein was demonstrated in both neuronal cells and in a murine model of neuronal toxicity. Furthermore, GLOD4 impaired neuronal connectivity and propagated preformed fibril (PFF)-induced α-syn aggregation in iPSC-derived dopaminergic neurons. In the A53T α-synuclein transgenic mouse models, GLOD4 knockout (KO) reduced paralysis and the PFF-induced spread of pathological α-syn. Overall, our results identify a novel function of GLOD4 as a mediator of α-syn nitration with implications in α-syn pathology and neurodegeneration. Therefore, understanding the role of GLOD4 and other nitrating enzymes in biology and diseases such as PD, cancer, and autoimmunity may unearth novel pathophysiological mechanisms and potential interventions.