Imaging spatial transcriptomics in a transgenic mouse model of α-synucleinopathy

ABSTRACT: One of the unifying pathological hallmarks of the age-related neurodegenerative disorders Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) is the presence of misfolded, aggregated, and often phosphorylated forms of the protein α-synuclein (α-syn) in neurons. α-syn pathology appears in select populations of neurons throughout various cortical and subcortical regions, and little is currently known about why some neurons develop pathology while others are spared. Here, we utilized subcellular-resolution imaging-based spatial transcriptomics (IST) in a transgenic mouse model which overexpresses wild-type human α-syn (α-syn-tg) to evaluate patterns of selective neuronal vulnerability to α-syn pathology. By performing post-run immunofluorescence for α-syn phosphorylated at Ser129 (pSyn), we identified cell types in the cortex and hippocampus of these mice which were vulnerable or resistant to developing pSyn pathology. Next, using a set of custom probes to detect genes involved in α-syn processing and toxicity, we investigated the transcriptional underpinnings of the observed selective vulnerability; this pointed to expression of the kinase-substrate pair Plk2, which phosphorylates α-syn at Ser129, and human SNCA (hSNCA), as a driving mechanistic force behind these neurons’ selective vulnerability to pSyn pathology in this model. Finally, we performed differential gene expression analysis, comparing non-transgenic cells to pSyn- and pSyn+ α-syn-tg cells; this revealed gene expression changes downstream of hSNCA overexpression and pSyn pathology which were conserved across cell types, including some genes which were differentially expressed in a pSyn-specific manner. This study provides one of the most comprehensive use cases of newly developed IST to date, yielding new biological insights into the formation of α-syn pathology and its downstream effects in a PD/DLB mouse model.

ORGANISM(S): Mus musculus

PROVIDER: GSE272303 | GEO | 2026/02/11

REPOSITORIES: GEO