Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology

A key hallmark of Parkinson's disease (PD) is Lewy pathology. Composed of alpha-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates. In the current study, we use spatial transcriptomics to capture whole transcriptome signatures from cortical neurons with alpha-synuclein pathology compared to neurons without pathology. We find, both in PD and related PD dementia, dementia with Lewy bodies and in the pre-formed fibril alpha-synucleinopathy mouse model, that specific classes of excitatory neurons are vulnerable to developing Lewy pathology. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. Neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and describe a conserved signature of molecular dysfunction in both mice and humans. The impact of alpha-synuclein aggregates on neurons has been unclear. Here, the authors identify a Lewy Associated Molecular Dysfunction from Aggregates (LAMDA) signature in inclusion bearing neurons in human brain and a mouse model of alpha-synucleinopathy.