Alpha-Synuclein Induces Brain Changes that Precede Locomotor Deficits

Post by Amanda McFarlan

What's the science?

Alpha-Synuclein (α-syn) is a soluble protein that is abundantly present in presynaptic neuronal terminals in the brain. α-syn is commonly found in a soluble form, however, it can also aggregate to form insoluble fibrils that play a key role in many neurodegenerative diseases including Parkinson’s disease and dementia with Lewy bodies. Imaging studies of synucleinopathies (diseases caused by an accumulation of α-syn aggregates) have provided new insight into how brain areas are affected by α-syn aggregates. However, it remains unknown how α-syn pathology causes changes in the brain over time. This week in The Journal of Neuroscience, Chu and colleagues used diffusion and functional magnetic resonance imaging (MRI) to investigate how an injection with α-synuclein fibrils affects the structure and function of the mouse brain over time.

How did they do it?

The authors performed bilateral intramuscular injections of either α-syn fibrils or phosphate-buffered saline (PBS, a control) in transgenic mice expressing the mutant human α-syn. They used MRI to collect images of these mice at 3 timepoints: pre-injection, 4 weeks post-injection, and 12 weeks post-injection. At each time point, the authors performed 4 different scans: an anatomical scan, a diffusion MRI (used to measure microstructural differences), sensory-evoked functional MRI (scan taken while applying 60 seconds of thermal heat stimulation on the mouse hind limb) and resting-state functional MRI (used to measure spontaneous activity across the brain and identify functionally correlated brain regions). The authors also assessed changes in locomotor activity at each time point using the rotarod task which measures the time it takes for a mouse to fall from a rotating rod. To extrapolate their findings, the authors used Cox proportional hazards regression models to determine which measurements were the most accurate for predicting survival time. 

What did they find?

The authors found that compared to control mice, mice injected with α-syn fibrils had reduced fractional anisotropy (a measure used in diffusion imaging that is thought to reflect fiber density, axonal diameter and myelination) in the cerebellum, vermis, anterior medulla, posterior medulla and somatosensory cortex at 4 weeks post-injection. Additionally, they determined that mice injected with α-syn fibrils had reduced fractional anisotropy compared to control mice in the pons and thalamus at 12 weeks post-injection. 

Mice injected with α-syn fibrils displayed no differences in blood-oxygen-level-dependent (BOLD) response pre-injection and at 4 weeks post-injection during the sensory-evoked MRI. However, at 12 weeks post-injection, mice injected with α-syn fibrils had a reduced BOLD response compared to control mice in the posterior medulla, anterior medulla, pons, and midbrain, suggesting that injection of α-syn fibrils reduced sensory activation. Mice injected with α-syn fibrils also had reduced fractional amplitude of low frequency fluctuations (ALFF, a measure of spontaneous activity at rest) compared to control mice in the midbrain, thalamus and striatum at 4 weeks post-injection. There were no differences in the latency to fall during the rotarod task, indicating that locomotor activity was not impaired in mice injected with α-syn fibrils compared to control mice. Lastly, using the regression models, the authors determined that a reduction in fractional anisotropy in the pons at 12 weeks post-injection was the greatest predictor of a lowered chance of survival.

What’s the impact?

This is the first study to show that structural and functional changes in the mouse brain that precede impairments to locomotor activity are detectable as early as 4 weeks following an intramuscular injection with α-syn fibrils. Notably, it was determined that survival time could be predicted by changes in fractional anisotropy in the pons. Together, these findings highlight the utility of diffusion and functional MRI in identifying markers of α-syn pathology in the brain. Understanding and improving these techniques may be especially relevant in clinical settings for detecting markers of synucleinopathies in human patients.

Chu et al. Alpha-synuclein induces progressive changes in brain microstructure and sensory-evoked brain function that precedes locomotor decline. The Journal of Neuroscience (2020). Access the original scientific publication here.