Glycated alpha-synuclein assemblies cause distinct Parkinsons disease pathogenesis in mice

Abstract

Alpha-synuclein (-Syn) misfolding and aggregation are key drivers of Parkinsons disease (PD) pathology. Mutations and certain post-translational modifications impact its aggregation propensity and pathogenicity. Glycation, a non-enzymatic modification enhanced during hyperglycemia and aging, both known risk factors for PD, has been implicated in -Syn pathology. Although preformed -Syn-fibrils induce PD-like phenotypes in mice, the impact of glycation on their pathogenicity is unclear. In the current study, we glycated -Syn using methylglyoxal (MGO), a potent glycating agent, resulting in altered biophysical characteristics in comparison to non-glycated -Syn. Glycation inhibited the formation of typical beta sheet structures under aggregating conditions. Despite that, glycated -Syn assemblies induced dopaminergic neurodegeneration and neuroinflammation to a similar extent as the non-glycated -Syn fibrils upon their injection in the mouse substantia nigra (SN). However, these glycated assemblies triggered higher neuroinflammation and increased accumulation of receptors for advanced glycation end products (RAGE) compared to non-glycated fibrils. Consequently, an earlier onset of neuromuscular deficits and anxiety was observed in these mice. Thus, glycation of -Syn causes distinct PD-associated pathology compared to non-glycated -Syn, causing an earlier onset of motor symptoms. These findings provide insight into how glycation of -Syn due to hyperglycemia may contribute to an increased risk of PD in diabetic populations.