Spreading alpha-Synuclein Oligomers Trigger Astrocyte Reactivity and Astrocyte-glutamatergic Neuron system dysfunction in an Age-Dependent Manner

Parkinson’s disease (PD) is characterized by the progressive accumulation and spatio-temporal spread of α-synuclein (α-syn) oligomers and a progressive loss of dopaminergic neurons. To investigate the transcriptional and cellular consequences of α-syn oligomer spreading, we employed spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a transgenic PD mouse model. We identified α-syn spreading to the substantia nigra and defined a transcriptional “Spreading Signature” associated with α-syn pathology. We found an age specific increase in reactive astrocytes, close interactions between reactive astrocytes and α-syn, and transcriptional dysregulation of the astrocyte-glutamatergic neuron network. We further identified two subtypes of glutamatergic neurons that are vulnerable to astrocytic changes. Comparative analysis with human PD snRNA-seq data revealed conserved astrocytic dysfunctions, underscoring the translational relevance of our findings. Based on our results, we propose a revised model of α-syn spreading and highlight 36 genes as potential therapeutic targets for mitigating astrocyte-neuron dysfunction in PD.