Inflammation of lymphatic vessels, which drain brain waste, may be involved in the onset of Parkinson’s disease. The condition is associated with the build-up of a misfolded protein called alpha-synuclein, which may not be efficiently removed from the brain if the lymphatic vessels are impaired. But the accumulation of alpha-synuclein seems to further damage these vessels, creating a self-reinforcing chain of events where each problem worsens the other.
“It is a vicious cycle,” says Justin Rustenhoven at the University of Auckland in New Zealand. This may also help explain why Parkinson’s disease is a progressive condition that worsens over time, he says.
Parkinson’s disease, which affects more than 10 million people worldwide, is characterised by a loss of neurons in brain regions that control movement. This causes symptoms such as tremor and muscle stiffness. The condition is thought to be caused by alpha-synuclein, which occurs naturally in the brain, misfolding and forming clumps that damage neurons.
In 2021, researchers showed that accumulation of alpha-synuclein in Parkinson’s disease may partly result from impaired drainage of brain waste via meningeal lymphatic vessels. These are found in the outermost layer of three membranes, called meninges, surrounding the brain. The vessels receive waste from a network of channels surrounding the brain’s blood vessels, called the glymphatic system, before transporting it to other parts of the body for disposal.
But what causes the lymphatic impairment in Parkinson’s disease was unknown. Rustenhoven and his colleagues wondered whether it may result from alpha-synuclein clogging up the meninges. “No one had really looked at that before,” says Rustenhoven, with most research focusing on changes to the regions that control movement, which are located deep within the brain.
The team analysed post-mortem samples of the meninges from seven people who’d had severe Parkinson’s disease and seven people who hadn’t had the condition. Only the Parkinson’s samples had alpha-synuclein clumps. “For the first time, we showed that these aggregates accumulate at the brain’s borders in people with Parkinson’s,” says Rustenhoven.
To determine whether such protein accumulation impairs clearance of brain waste, the researchers injected mice with a virus that infected cells called fibroblasts in the meninges. This caused them to continually produce alpha-synuclein at elevated levels, similar to those seen in people with Parkinson’s disease. At such high levels, alpha-synuclein misfolded and formed toxic clumps that spread across cells in lymphatic vessels in the meninges, but not inside the brain.
Two months later, brain imaging revealed that these mice’s meningeal lymphatic vessels drained waste fluid half as rapidly as those of control mice, which were injected with a virus encoding for an inert protein. What’s more, in the former group of mice, immune cells called macrophages had engulfed the alpha-synuclein clumps at the brain’s borders. This caused the macrophages to double in number and produce about triple the amount of TNF-alpha, an inflammatory molecule.
Next, the team exposed sheets of human cells, found in meningeal lymphatic vessels, to either alpha-synuclein or TNF-alpha. Both molecules caused gaps to form between the lymphatic cells, making them leaky, says Rusterhoven.
“The accumulation of alpha-synuclein in the brain borders basically drives an immune response that pokes holes in those lymphatic vessels, making them ineffective at draining,” he says. “We already know from other studies that those lymphatics are important for draining alpha-synuclein, so impaired lymphatic drainage [due to alpha-synuclein] means even more of the protein is going to build up.”
This feedback loop keeps reinforcing itself, which may cause the worsening of brain damage and symptoms associated with Parkinson’s, says Rusterhoven.
The same mechanism probably applies to other neurodegenerative conditions where proteins accumulate, such as Alzheimer’s disease, says Camille Carroll at Newcastle University in the UK. But this understanding also creates new treatment opportunities. It suggests that “therapies that dampen or modulate that immune response could prevent lymphatic dysfunction to treat Parkinson’s”, says Rusterhoven.
The team now plans to carry out similar experiments where mice are studied after they develop Parkinson’s symptoms, not just its associated brain changes. These mice will also be tracked for longer, he says.
“Their mouse model was appropriate for the question they were asking, which was looking specifically at the effects of alpha-synuclein at the brain border on lymphatics,” says Carroll. “But linking their findings to symptoms will be important.”
In ongoing work, the researchers are collecting more brain-border samples from people who died with Parkinson’s disease of varying severity. This will enable them to determine how often alpha-synuclein clogs up the brain’s borders during the condition and at what stage it may start causing lymphatic impairment.
They are also trialling, in mice and human cells, whether drugs that block TNF-alpha can reverse lymphatic damage during Parkinson’s. A prior study looked at people with inflammatory bowel disease, which is linked to a higher risk of Parkinson’s, and found that those who took drugs that block TNF-alpha were 78 per cent less likely to develop Parkinson’s.
An ongoing trial is also giving people with REM (rapid eye movement) sleep behaviour disorder, which often precedes Parkinson’s disease, a drug that blocks TNF-alpha, to determine whether this affects Parkinson’s progression. “This will be very interesting evidence to support our findings,” says Rustenhoven.