The O-Glycome of Human Nigrostriatal Tissue and Its Alteration in Parkinson’s Disease

O -Glycosylation changes in misfolded proteins are of particular interest in understanding neurodegenerative conditions such as Parkinson's disease (PD) and incidental Lewy body disease (ILBD). This work outlines optimizations of a microwave-assisted nonreductive release to limit glycan degradation and employs this methodology to analyze O -glycosylation on the human striatum and substantia nigra tissue in PD, ILBD, and healthy controls, working alongside well-established reductive release approaches. A total of 70 O -glycans were identified, with ILBD presenting significantly decreased levels of mannose-core ( p = 0.017) and glucuronylated structures ( p = 0.039) in the striatum and PD presenting an increase in sialylation ( p < 0.001) and a decrease in sulfation ( p = 0.001). Significant increases in sialylation ( p = 0.038) in PD were also observed in the substantia nigra. This is the first study to profile the whole nigrostriatal O -glycome in healthy, PD, and ILBD tissues, outlining disease biomarkers alongside benefits of employing orthogonal techniques for O -glycan analysis.