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

Abstract

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.

Oligodendrocytes, a New Player in the Etiology of Parkinson's Disease

“…Agarwal and colleagues 3 performed single‐cell transcriptomics of the SN and the cortex of 5 human postmortem brains and matched their data with the genetic variants contributing to 30 different human complex traits (pertaining to different categories such as autoimmune diseases, neurological disorders, and neuro‐psychiatric disorders). They found nonoverlapping associations of PD genetic risk with dopaminergic neurons, oligodendrocytes (also found in an independent study using mouse transcriptomic data 4 ), and oligodendrocyte precursor cells (OPCs), proposing distinct PD‐associated cell etiologies within the SN.…”

“…There is growing evidence that for many brain disorders, glial cells may causally contribute to neuronal alterations. Agarwal and colleagues 1 described a human single‐nuclei transcriptomic atlas for the substantia nigra (SN) and found a striking association between Parkinson's disease (PD) risk and oligodendrocyte‐specific gene expression, suggesting that oligodendrocytes could play a causal role in the disease. The authors' aim was to study cell‐type‐specific gene expression in the human SN to identify the potential contributions of the different cell types to PD and other neurological disorders because in other neurodegenerative diseases such as Alzheimer's disease (AD), the cell type associated with the genetic risk (microglia) is not the cell type directly associated with the disease symptoms (loss of neurons) 2 .…”

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases

“…Despite glial cells having been reported to induce deregulation in mitochondria and endoplasmic reticulum dysfunction resulting in bioenergetic and Ca 2+ homeostasis disruption [ 99 ], neuroinflammation is critical for AD since it appears to modulate the disease progression [ 100 , 101 ]. The integration of the immune system and the central nervous system was recently reviewed [ 102 ].…”

“…Among other functions, the key role of the microglia consists of the regulation of inflammation, synaptic connectivity, programed cell death, wiring and circuitry formation, phagocytosis of cell debris, and synaptic pruning and sculpting of postnatal neural circuits [ 110 ]. Research identified a correlation of specific expression patterns in microglia from the brain cortex and AD risk variations, indicating that neuroinflammation may have a more important role in AD than in other neuropsychiatric diseases [ 99 ]. It was revealed that inflammatory pathways are also linked to rapid cognitive decline in the mild cognitive impairment stage of AD [ 18 ].…”

Association of a Common Genetic Variant with Parkinson’s Disease is Propagated through Microglia

“…Approaches that nominate enrichment in specific cell types have been useful in identifying likely genes as most tissues have heterogeneous cellular composition. Several approaches have nominated dopamine neurons (4)(5)(6)(7), which are principal cell types lost in PD, as mediators of neurodegeneration, although other studies have identified non-neuronal cells including oligodendrocytes and oligodendrocyte precursor cells (4,8) as contributing to disease risk. Such approaches rely on the presumed mechanism that non-coding variants affect gene expression, which can be inferred by mapping expression quantitative trait loci (eQTL).…”