Inflammation of lymphatic vessels that drain waste from the brain may drive Parkinson's disease through a self-reinforcing cycle, according to research by Justin Rustenhoven at the University of Auckland and colleagues published in the Journal of Experimental Medicine.
The study shows that alpha-synuclein, a misfolded protein linked to Parkinson's, accumulates at the brain's borders in people with the condition. Rustenhoven's team analyzed post-mortem meninges samples from seven people with severe Parkinson's disease and seven without it. Only the Parkinson's samples contained alpha-synuclein clumps.
In mouse experiments, researchers infected meningeal cells with a virus that produced elevated levels of alpha-synuclein similar to those in Parkinson's patients. Two months later, the mice's meningeal lymphatic vessels drained waste fluid at half the rate of control mice. Alpha-synuclein clumps spread across lymphatic vessel cells, triggering immune cells called macrophages to engulf them. These macrophages doubled in number and produced three times more TNF-alpha, an inflammatory molecule.
When human lymphatic vessel cells were exposed to either alpha-synuclein or TNF-alpha in the lab, gaps formed between the cells, making them leaky. "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," Rustenhoven says. Since impaired lymphatic drainage means more alpha-synuclein builds up, the cycle reinforces itself and may explain why Parkinson's worsens over time.
Camille Carroll at Newcastle University notes the findings may apply to other neurodegenerative conditions involving protein accumulation, such as Alzheimer's disease. Rustenhoven says therapies that dampen the immune response could prevent lymphatic dysfunction.
The team plans to study mice after they develop Parkinson's symptoms rather than just associated brain changes, and will track them longer. They are also collecting more brain-border samples from people with varying Parkinson's severity and testing whether TNF-alpha-blocking drugs can reverse lymphatic damage in mice and human cells. An ongoing trial is giving people with REM sleep behavior disorder, which often precedes Parkinson's, a TNF-alpha-blocking drug to determine whether it affects disease progression.