By transcriptomic profiling of more than 300,000 cells in the human substantia nigra, a part of the brain that helps control body movements, researchers at Mount Sinai in New York, United States, have identified a new type of neuron that exhibits vulnerability in Parkinson’s disease and has not been previously described in this pathology. This new discovery could help explain the complexity of the disease’s symptoms and guide the development of new therapies.
The pathology of Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Until now it was not clear whether other cell types besides neurons in this brain region show vulnerability in Parkinson’s disease.
By transcriptomic profiling of 315,867 high-quality single nuclei in the substantia nigra from people with and without Parkinson’s, the Mount Sinai team identified clusters of cells representing different types of neurons, glia, endothelial cells, pericytes, fibroblasts, and T cells, and investigated cell type-dependent changes in gene expression in Parkinson’s disease.
Notably, a unique group of neurons marked by expression of RIT2, a Parkinson’s risk gene, also showed vulnerability in Parkinson’s disease.
The team validated this human finding of RIT2-enriched neurons in both mesencephalic organoids and the substantia nigra of mice.
Results demonstrate distinct transcriptomic signatures of RIT2-enriched neurons in the human substantia nigra and implicate reduced RIT2 expression in the pathogenesis of Parkinson’s disease.
The recent study clarifies the diversity of cell types, including dopaminergic neurons, in the substantia nigra and the complexity of molecular and cellular changes associated with the pathogenesis of Parkinson’s disease.
The study establishes a transcriptomic atlas of the human substantia nigra at single-cell resolution and delineates the landscape of molecular and cellular changes in Parkinson’s disease.
This not only provides a valuable resource for the molecular and cellular composition and structures of the human substantia nigra, but also presents an unprecedented opportunity to deeply understand pathogenic mechanisms, identify key therapeutic targets, and develop clinical biomarkers for Parkinson’s disease, the authors write in their conclusions.
In the study, the researchers studied postmortem brain tissue from Parkinson’s disease patients, organoids derived from human stem cells, and animal models.
The average age of the postmortem brains was 81 years.
“We were surprised to discover a type of neuron with vulnerability in Parkinson’s disease that had never been described before”stated Dr. Zhenyu Yue from Mount Sinai about this research.
The researchers also studied the remaining dopamine neurons in advanced stages of the disease for clues as to how they adapt and survive, while the vast majority of dopamine neurons are lost.
Equally significant is the identification of molecular changes in different types of brain cells in Parkinson’s disease.
These findings provide not only deep insight into the pathogenic mechanisms underlying the disease, but also vital therapeutic targets for this devastating disease, write the authors, who state that the study helps solve a fundamental problem in addressing brain diseases by elucidating the diversity and unique nature of brain cells.
The study was recently published in January in the journal Science Advances.
2024-01-26 06:59:51
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