This study investigates the molecular changes associated with Lewy pathology in cortical neurons of Parkinson's disease (PD) brains and a mouse model of α-synucleinopathy. Using spatial transcriptomics, the researchers identified specific classes of excitatory neurons, particularly layer 5 intratelencephalic (IT) and layer 6b neurons, as being vulnerable to developing Lewy pathology. They also identified a conserved gene expression signature, designated as the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature, in these neurons. This signature includes downregulation of synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes, and upregulation of DNA repair and complement/cytokine genes. The study highlights the selective vulnerability of certain neuron types to Lewy pathology and provides insights into the molecular mechanisms underlying this process.This study investigates the molecular changes associated with Lewy pathology in cortical neurons of Parkinson's disease (PD) brains and a mouse model of α-synucleinopathy. Using spatial transcriptomics, the researchers identified specific classes of excitatory neurons, particularly layer 5 intratelencephalic (IT) and layer 6b neurons, as being vulnerable to developing Lewy pathology. They also identified a conserved gene expression signature, designated as the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature, in these neurons. This signature includes downregulation of synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes, and upregulation of DNA repair and complement/cytokine genes. The study highlights the selective vulnerability of certain neuron types to Lewy pathology and provides insights into the molecular mechanisms underlying this process.