Alpha-Synuclein Propagation Via Brain Lymphatic System in Parkinson's Disease

In numerous neurodegenerative conditions, there is a progressive accumulation and spreading of abnormal proteins within the brain. The question arises: Which occurs first, the aggregation or the propagation? Researchers from Japan have provided fresh insights into the mechanism underlying Parkinson's disease. Their recent study, featured in Cell Reports, conducted by scientists from Tokyo Medical and Dental University (TMDU), demonstrates that a mutated variant of a protein known as α-synuclein disseminates to various cerebral regions via the lymphatic system before undergoing aggregation.

While the precise role of α-synuclein remains incompletely understood, it is known to play a part in neurotransmission. However, in certain neurodegenerative disorders like Parkinson’s disease, α-synuclein undergoes a structural transformation and gives rise to pathological clumps.

“Most experiments conducted so far only used fibrils, which are the clumps formed when monomeric α-synuclein aggregates. The fibrils are transmitted from neurons to neurons, but it remains unclear whether monomers act in the same way,” explains Kyota Fujita, an author of the study.

To further investigate how monomers and fibrils of α-synuclein move around in the brain, the researchers injected small amounts of viral particles into the orbital cortex of mice to produce fluorescent monomeric mutant α-synuclein. Because any cell type can contribute to α-synuclein propagation, they used viral particles to enable the synthesis of α-synuclein monomers in all cell types present in the injection area. This method ensured that all modes of propagation were accounted for (1^✔ ✔Trusted Source
Mutant α-synuclein propagates via the lymphatic system of the brain in the monomeric state

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Twelve months after the injection, although the fluorescent signal was lower in the injected region, signals were detected in other brain areas. Interestingly, fluorescent α-synuclein was detected in remote regions two weeks after injection, indicating an early spreading of mutant α-synuclein in the brain.

How did α-Synuclein Propagate?

The team followed the three-dimensional distribution of α-synuclein in the brain and found fluorescent α-synuclein in the glymphatic system, which is the lymphatic system of the brain. The glymphatic system is involved in draining and renewing fluid from the brain and eliminating toxins, but it can also distribute toxic substances throughout the brain. The team also observed the presence of fluorescent α-synuclein in the matrix surrounding neurons and in the cytosol of neurons. This finding suggested that fluorescent α-synuclein was taken up by the extracellular matrix and, subsequently, by neurons.

The researchers also investigated the aggregation state of α-synuclein in the remote brain regions. “Fibrils of α-synuclein formed after the monomers had propagated,” says Professor Hitoshi Okazawa, the research group leader. “Specifically, we observed α-synuclein monomer in the glymphatic system and remote regions as early as two weeks after injection, while we found α-synuclein fibrils 12 months after injection!”

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The amount of α-synuclein aggregated and the time at which they formed after injection varied among regions and were not proportional to the distance from the injection site. This observation is consistent with the known vulnerability of some regions to pathological α-synuclein.

This study shows how monomeric α-synuclein propagates through the glymphatic system in a different way from the fibrils. Thus, targeting these early events, α-synuclein monomer, and the brain lymphatic system may limit the progression of Parkinson’s disease.

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Reference:

1. Mutant α-synuclein propagates via the lymphatic system of the brain in the monomeric state - (https://pubmed.ncbi.nlm.nih.gov/37591248/)

Source-Eurekalert