A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders.

Agarwal D., Sandor C., Volpato V., Caffrey TM., Monzón-Sandoval J., Bowden R., Alegre-Abarrategui J., Wade-Martins R., Webber C.

We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinson's disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer's disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.

DOI

10.1038/s41467-020-17876-0

Type

Journal article

Journal

Nat Commun

Publication Date

21/08/2020

Volume

11

Keywords

Alzheimer Disease, Astrocytes, Brain, Dopaminergic Neurons, Gene Expression, Humans, Microglia, Mitochondria, Nervous System Diseases, Parkinson Disease, Substantia Nigra, Transcriptome

Permalink Original publication