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Mouse-brain model maps spread of alpha-synuclein in Parkinson's disease

Misfolded protein aggregates are found in the brains of people with many neurodegenerative diseases, but exactly how these proteins spread from cell to cell and damage the brain is not well understood. A new computational mouse model mapped alpha-synuclein, a misfolded protein found in Parkinson’s and related diseases, as it spread through the brain. Described in a study funded in part by NIA and published in Nature Neuroscience, the model is the first to incorporate both brain connectivity and genetic risk factors involved in abnormal alpha-synuclein spread.

model of spread of alpha-synuclein in a mouse brain
Spread of alpha-synuclein pathology from a single injection site (dark orange) on the right hemisphere of a mouse brain and a network model of that spread on the left. Courtesy of Michael X. Henderson, Ph.D., University of Pennsylvania

Scientists from the University of Pennsylvania, Philadelphia, and its NIA-funded Alzheimer’s Disease Research Center, injected alpha-synuclein into the brains of 3-month-old mice and analyzed the protein accumulations after one, three, and six months. They found that alpha-synuclein accumulated distinctly in different brain regions, with higher concentrations in areas connected to the injection site.

To understand the spread of alpha-synuclein in more detail, the researchers created a computer-based “network diffusion” model using a map of mouse brain regions and connecting pathways. Comparing the protein accumulations from the mouse brains to the model, they observed that the protein spread primarily along specific brain pathways. However, certain areas of alpha-synuclein accumulation occurred outside those pathways. Those areas were linked to higher expression of SNCA, the gene that encodes alpha-synuclein, leading the researchers to incorporate SNCA expression into their computer model.

The final result—a brain network model that visualizes alpha-synuclein spreading based on brain connectivity and gene expression—provides a new method to “test different hypotheses of spreading patterns, timing, directionality and vulnerability,” according to an accompanying editorial.

NIA recently awarded the research team a grant (U19AG062418) to further explore the spread of alpha-synuclein proteins and how this process can lead to specific neurodegenerative disease, including Alzheimer’s disease and Parkinson’s disease. With advances in human imaging and data collection, researchers could someday develop a similar model to study the spread of abnormal proteins in the human brain.

This research was funded in part by NIA grants T32AG000255 and P30AG010124.

References:

Henderson MX, et al. Spread of α-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nature Neuroscience. 2019;22(8):1248–1257. doi: 10.1038/s41593-019-0457-5.

Kuhl E. Connectomics of neurodegeneration. Nature Neuroscience. 2019;22(8):1200-1202. doi: 10.1038/s41593-019-0459-3.