Imaging spatial transcriptomics reveals molecular patterns of vulnerability to pathology in a transgenic α-synucleinopathy model.

In Parkinson's disease and dementia with Lewy bodies, aggregated and phosphorylated α-synuclein pathology appears in select neurons throughout cortical and subcortical regions, but little is currently known about why certain populations are selectively vulnerable. Here, using imaging spatial transcriptomics (IST) coupled with downstream immunofluorescence for α-synuclein phosphorylated at Ser129 (pSyn) in the same tissue sections, we identified neuronal subtypes in the cortex and hippocampus of transgenic human α-synuclein-overexpressing mice that preferentially developed pSyn pathology. Additionally, we investigated the transcriptional underpinnings of this vulnerability, pointing to expression of , which phosphorylates α-synuclein at Ser129, and human (), as key to pSyn pathology development. Finally, we performed differential expression analysis, revealing gene expression changes broadly downstream of overexpression, as well as pSyn-dependent alterations in mitochondrial and endolysosomal genes. Overall, this study yields new insights into the formation of α-synuclein pathology and its downstream effects in a synucleinopathy mouse model.