Alpha-synuclein induced immune response triggers Parkinson’s disease

Parkinson's disease has been characterized by the significant role that alpha-synuclein and immune activation play in driving disease progression. Moreover, the immunogenicity of alpha-synuclein-derived epitopes in driving both innate and adaptive immunity has been discovered in prodromal Parkinson's disease. Despite these findings, the mechanistic role of the immune system in contributing to disease ontogenesis remains unknown. Recent evidence has identified alpha-synuclein as a candidate biomarker, with seed amplification assays yielding high sensitivity for sporadic cases of the disease. Performing a metanalysis correlating patient’s individual positive assays with immune activity and appearance of symptoms across time, we found associations between these three parameters. We therefore speculated that the specific alpha-synuclein peptide (a-syn61-75) associated with immune CD4+ T cells in idiopathic patients could underlie Parkinson’s disease development. To examine how the interaction of alpha-synuclein and a specific immune response participates to Parkinson’s disease ontogenesis, we designed a novel auto-immune alpha-synuclein induced model of Parkinson's disease. This model immunizes wildtype mice to alpha-synuclein by peripheral injection in adjuvant. We demonstrate that autoimmunity mediated by CD4+T cell activation with alpha-synuclein a-syn61-75 antigen is required to lead to immune cell brain infiltration and localized inflammation in the substantia nigra, triggering dopaminergic cell neurodegeneration and deficits in locomotion and gait kinematics. Our findings uncover a causal link between immune cells and alpha-synuclein in driving Parkinson's disease pathogenesis. This study provides the basis for temporally tracking symptom development, exploring preventive strategies and prodromal therapeutic interventions in Parkinson’s Disease.