The multi-omic landscape of oligodendrocytes in Multiple System Atrophy

Multiple System Atrophy (MSA) is a detrimental and progressive Parkinsonian disorder affecting movement and the autonomic nervous system. Signs and symptoms of autonomic dysfunction include problems in bladder control, bowel movement, sleep, and sexual function. Currently, no treatments are available to slow or halt the progression of the disease. This is due to our limited understanding of the mechanisms that lead to the development of MSA, characterized by profound loss of nerve cells accompanied by increased glial cells. One cell type of glia, oligodendrocytes – the myelinating cells of the brain that provide support and insulation to axons of nerve cells – are of particular interest since these cells show accumulation of a distinct protein called alpha-synuclein.

The interaction of how alpha-synuclein accumulation and oligodendrocyte function is not well understood. Importantly, detailed information on the gene expression profiles, epigenetic landscapes, and intercellular communication between oligodendrocytes with or without alpha-synuclein inclusions and their neighboring cells is very limited. To overcome this roadblock to potentially new treatment avenues, we propose to isolate oligodendrocytes from human postmortem brain tissue from MSA and control patients. We will perform single nuclei transcriptomics on oligodendrocytes to identify the presence of potential subpopulations that may be implicated in the pathogenesis of MSA. Next, we will identify genes that are aberrantly regulated in oligodendrocytes in MSA and determine transcription factors that drive the gene expression program of these cells.

Lastly, to obtain spatial resolution and changes in the intercellular communication between oligodendrocytes, neurons, and other brain cell types, we will perform spatial transcriptomics, which allows us to map gene activity in single cells in the putamen. Collectively, our innovative approach leveraging human postmortem brain samples from MSA patients has the potential to define novel therapeutic avenues to alter the course of the disease.