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

BackgroundParkinsons disease (PD) is characterized by the progressive accumulation and spatio-temporal spread of -synuclein (-syn) oligomers and a progressive loss of dopaminergic neurons. Many studies showed a direct cytotoxic effect of -syn oligomers on neurons. Other cell types including astrocytes were also reported to show specific responses to -syn and are believed to play a role in the spreading of PD pathology. MethodsTo investigate the transcriptional and cellular consequences of -syn oligomer spreading, we employed spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a transgenic PD mouse model expressing human -syn in neurons. We further compared our findings to published public snRNA-seq datasets from human PD patients ResultsOur analysis identified -syn spreading mostly to the substantia nigra and defined a transcriptional "Spreading Signature" associated with -syn pathology. We found an age correlated increase in astrocytes, close interactions between astrocytes and -syn, and transcriptional dysregulation of the astrocyte-glutamatergic neuron axis. We further identified two subtypes of glutamatergic neurons that are vulnerable to astrocytic changes. Comparative analysis with human PD snRNA-seq data showed concordant transcriptional changes related to astrocytic dysfunctions and diminished neuronal signaling. ConclusionBased on our results, we propose a model of -syn oligomer spreading involving astrocytes, glutamatergic synapses, and a disturbance in the astrocyte-glutamatergic neuron axis.