Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology. Parkinson's disease (PD) is characterized by Lewy pathology, composed of α-synuclein, found in dopaminergic neurons and cortical regions. This study uses spatial transcriptomics to analyze whole transcriptome signatures of cortical neurons with α-synuclein pathology compared to those without. It identifies specific classes of excitatory neurons vulnerable to developing Lewy pathology, and a conserved gene expression signature, termed the Lewy-associated molecular dysfunction from aggregates (LAMDA), in aggregate-bearing neurons. These neurons downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes, while upregulating DNA repair and complement/cytokine genes. The study shows that neurons with α-synuclein inclusions exhibit molecular dysfunction similar to the α-synucleinopathy mouse model, with over 600 conserved gene expression changes. The results indicate a selectively vulnerable population of neurons in the PD cortex, with α-synuclein inclusions associated with a strong and conserved stress response. The study also identifies that α-synuclein pathology is enriched in layer 5 intratelencephalic (IT) and layer 6b neurons. These findings highlight the molecular mechanisms underlying Lewy pathology and suggest potential therapeutic targets for PD.Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology. Parkinson's disease (PD) is characterized by Lewy pathology, composed of α-synuclein, found in dopaminergic neurons and cortical regions. This study uses spatial transcriptomics to analyze whole transcriptome signatures of cortical neurons with α-synuclein pathology compared to those without. It identifies specific classes of excitatory neurons vulnerable to developing Lewy pathology, and a conserved gene expression signature, termed the Lewy-associated molecular dysfunction from aggregates (LAMDA), in aggregate-bearing neurons. These neurons downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes, while upregulating DNA repair and complement/cytokine genes. The study shows that neurons with α-synuclein inclusions exhibit molecular dysfunction similar to the α-synucleinopathy mouse model, with over 600 conserved gene expression changes. The results indicate a selectively vulnerable population of neurons in the PD cortex, with α-synuclein inclusions associated with a strong and conserved stress response. The study also identifies that α-synuclein pathology is enriched in layer 5 intratelencephalic (IT) and layer 6b neurons. These findings highlight the molecular mechanisms underlying Lewy pathology and suggest potential therapeutic targets for PD.