Mitochondrial oxidant stress promotes alpha-synuclein aggregation and spreading in mice with mutated glucocerebrosidase

Abstract

Mutations of the glucocerebrosidase-encoding gene, GBA1, are common risk factors for Parkinsons disease. Although only a minority of mutation-carrying individuals develops the disease, the mechanisms of neuronal vulnerability predisposing to pathology conversion remain largely unclear. In this study, heterozygous expression of a common glucocerebrosidase variant, namely the L444P mutation, was found to exacerbate -synuclein aggregation and spreading in a mouse model of Parkinson-like pathology targeting neurons of the medullary vagal system. These neurons are primary sites of -synuclein lesions in Parkinsons disease and were shown here to become more vulnerable to oxidative stress after L444P expression. Nitrative burden paralleled the enhanced formation of reactive oxygen species within vagal neurons expressing mutated glucocerebrosidase, as indicated by pronounced accumulation of nitrated -synuclein. A causal relationship linked mutation-induced oxidative stress to enhanced -synuclein pathology that could indeed be rescued by neuronal overexpression of the mitochondrial antioxidant enzyme superoxide dismutase 2. Further evidence supported a key involvement of mitochondria as sources of reactive oxygen species as well as targets of oxidative and nitrative damage within L444P-expressing neurons. Scavenging of oxygen species by superoxide dismutase 2 effectively counteracted deleterious nitrative reactions and prevented nitrated -synuclein burden. Taken together, these findings support the conclusion that enhanced vulnerability to mitochondrial oxidative stress conferred by glucocerebrosidase mutations should be considered an important mechanism predisposing to Parkinsons disease pathology, particularly in brain regions targeted by -synuclein aggregation and involved in -synuclein spreading.