Summary: Enteric neurons appear to play a key role in the development of Parkinson’s disease. The findings support the hypothesis and previous studies that the neurodegenerative disease may start in the gut before spreading to the brain. Researchers also found oligodendrocytes were affected during the early stages of Parkinson’s, even before the loss of dopaminergic neurons.
Source: Karolinska Institute
Researchers at Karolinska Institutet in Sweden and the University of North Carolina in the USA have mapped out the cell types behind various brain disorders. The findings are published in Nature Genetics and offer a roadmap for the development of new therapies to target neurological and psychiatric disorders. One interesting finding was that cells from the gut’s nervous system are involved in Parkinson’s disease, indicating that the disease may start there.
The nervous system is composed of hundreds of different cell types with very different functions. It is vital to understand which cell types are affected in each disorder so as to understand the causes of the disorders and, ultimately, develop new treatments.
Researchers have now combined mice gene expression studies with human genetics to systematically map cell types underlying various brain disorders, including Parkinson’s disease, a neurodegenerative disorder with cognitive and motor symptoms resulting from the loss of dopamine-producing cells in a specific region of the brain.
“As expected, we found that dopaminergic neurons were associated with Parkinson’s disease. More surprisingly, we found that enteric neurons also seem to play an important role in the disorder, supporting the hypothesis that Parkinson’s disease starts in the gut,” says one of the study’s main authors Patrick Sullivan, Professor at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and Yeargan Distinguished Professor at the University of North Carolina.
When the researchers analysed differences in brain tissue from healthy individuals and people with Parkinson’s disease at different stages of the disease, they made another unexpected discovery. A type of support cell in the brain called oligodendrocytes were found to be affected early on, suggesting that they play a key role in the early stages of the disease.
“The fact that the animal studies pointed us to oligodendrocytes and that we were then able to show that these cells were also affected in patients suggests that the results may have clinical implications,” says Jens Hjerling-Leffler, research group leader at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and the other main author of the study.
The oligodendrocytes appear to be affected even before the loss of dopaminergic neurons.
“This makes them an attractive target for therapeutic interventions in Parkinson’s disease,” says Julien Bryois, researcher at the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet and one of the first authors of the study.
The study was financed by the Swedish Research Council, StratNeuro, the Wellcome Trust, the Swedish Brain Foundation, the Swiss National Science Foundation, the US National Institute of Mental Health, and the Psychiatric Genomics Consortium.
Patrick Sullivan reports that he is currently a member of the pharmaceutical company Lundbeck’s advisory committee and that he has received grants from them. For the past three years he has been a member of Pfizer’s scientific advisory board and received fees from Element Genomics and Roche. Co-author Cynthia Bulik has received grants from Shire and is a member of their scientific advisory board. She is also an author and recipient of royalties from both Pearson and Walker.
Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease.