Single-cell profiling of limbic excitatory neurons reveals dysregulation of metabolic pathways in Parkinson’s disease

Parkinson’s disease (PD) is a common age-related neurodegenerative disorder that is pathologically characterized by the presence of Lewy bodies within neurons across several brain regions. Although the severe, selective degeneration of pigmented dopaminergic neurons in the midbrain results in a characteristic constellation of motor symptoms, how additional neuronal populations are affected in disease and contribute to neuropsychiatric symptoms remains unclear. The amygdala is one of the most frequent brain regions to harbor Lewy bodies in both PD and Alzheimer’s disease with co-existing alpha-synuclein pathology. To understand how neurons and glial cells are altered in this subcortical limbic area in PD, we performed single-nucleus RNA-sequencing (snRNA-seq) of patients and age-matched controls that yielded 168,270 transcriptomes following quality control measures. Through stringent differential gene expression analysis, we found transcriptional perturbations of genes linked to metabolic pathways in excitatory neurons, including upregulation of TFEB, but not inhibitory neurons or neural precursors. Additionally, we observed increased microglia with shifts towards activated states. Through bioinformatic integration of snRNA-seq with genetics studies, our findings suggest that PD risk factors act in cell-autonomous processes through both limbic excitatory neurons and midbrain dopaminergic neurons. Our findings define the selective vulnerability of excitatory neurons in the amygdala and may have implications for the understanding and treatment of non-movement symptoms in PD.