Post by Shireen Parimoo
What's the science?
Misfolding of α-synuclein protein is thought to underlie neurological disorders like dementia with Lewy bodies and Parkinson’s disease. As Parkinson’s disease progresses, Lewy bodies composed of misfolded α-synuclein are found in an increasing number of brain regions. However, little is known about how α-synuclein pathology spreads through the brain over time. Research in rodents has found that injecting misfolded α-synuclein directly into the brain can induce the aggregation of the rodent's own α-synuclein into Lewy body-like aggregates, eventually leading to neuronal loss. Additionally, people with a G2019S mutation in the LRRK2 gene have an increased risk of getting Parkinson’s disease, but not everyone with this mutation goes on to develop Parkinson’s disease. Thus, it is unclear how this genetic risk factor interacts with α-synuclein pathology in the development of disease. This week in Nature Neuroscience, Henderson and colleagues quantified the spatiotemporal spread of α-synuclein pathology in non-transgenic mice and examined the effect of the G2019S LRRK2 mutation in transgenic “at-risk” mice.
How did they do it?
The authors injected pre-formed α-synuclein fibrils into the dorsal striatum of non-transgenic mice and mice with the G2019S LRRK2 mutation. α-Synuclein pathology was then quantified using immunohistochemistry one, three, or six months after the injection in 172 regions throughout the brain. A separate quantitative algorithm allowed the authors to develop a measure of neuron loss based on Lewy body loss over time, which was validated by counting the number of dopamine neurons lost in mice (detected by tyrosine hydroxylase antibodies). This experiment generated the first quantitative map of α-synuclein pathology in mice.
To further understand factors which impact the spread of α-synuclein pathology, the authors generated a network diffusion model that makes predictions about how pathology would spread along the axonal connections between regions. As a means of validation, they also tested several other models which predict spread based on 1) how close regions are to each other, 2) only anterograde (forward from neuron cell bodies to presynaptic terminals) connections, 3) a mixed-up connection map or 4) simulated injections from other regions. Finally, they measured relative vulnerability of brain regions to pathology by comparing the data to the model’s predictions. The reasoning behind this approach is that if there is more pathology in a given region than the model predicts, then that region is more vulnerable. Conversely, if there is less pathology than predicted by the model, then those regions are more resilient to α-synuclein pathology.
What did they find?
In non-transgenic mice, α-synuclein fibril injection induced reproducible spatiotemporal patterns of α-synuclein pathology in many regions of the brain, including the vulnerable substantia nigra. Neuronal death was observed primarily in the ipsilateral substantia nigra, which contains the dopamine neurons most affected in Parkinson’s disease. The network model based on retrograde connectivity (backwards from the synapse to neuron cell bodies) showed the best fit to actual pathology data, suggesting that these connections form the major pathway for pathology spread. Using this model, the authors found that thalamic nuclei were among the most resilient to pathology, and the amygdala and the piriform cortex were among the most vulnerable. These vulnerability measures correlated with α-synuclein gene expression, meaning that both the anatomical connectivity of brain areas and their gene expression profiles are important determinants of α-synuclein pathology. Interestingly, a different pattern was observed in G2019S LRRK2 transgenic mice, and pathology increased selectively in regions that were resilient in non-transgenic mice, indicating that the spread of α-synuclein pathology varies in the presence of genetic risk factors.
What's the impact?
This study is the first to quantify the spread of misfolded α-synuclein throughout the brains of non-transgenic and transgenic mouse models of Parkinson’s disease, and to generate a network model that can predict how α-synuclein pathology spreads. The final model, which predicts how pathology will spread through the brain based on anatomical connectivity and α-synuclein gene expression, provides a valuable tool for investigating the impact of genetic risk factors, understanding regional vulnerability and estimating the efficacy of therapeutic interventions.
Henderson et al. Spread of α-synuclein pathology throughout the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nature Neuroscience (2019). Access the original scientific publication here.