Scientists uncover kidney-to-brain route for Parkinson’s-related protein spread

A new study published in Nature Neuroscience has uncovered evidence that Parkinson’s disease and related conditions may start not in the brain, but in the kidneys. Researchers found that a key protein involved in the development of these diseases, called alpha-synuclein, can build up in the kidneys and travel to the brain through nerve pathways—especially when kidney function is impaired. The findings suggest that chronic kidney disease may increase the risk of Parkinson’s by allowing toxic protein deposits to accumulate and spread into the central nervous system.

Parkinson’s disease is a progressive neurological disorder that affects movement, coordination, and a range of non-motor functions. The most recognizable symptoms include tremors, muscle rigidity, slowness of movement, and postural instability. These symptoms arise primarily because of the loss of dopamine-producing neurons in a brain region called the substantia nigra. Dopamine is a chemical messenger that plays a key role in motor control, and its depletion leads to the hallmark motor problems of the disease.

But Parkinson’s is not limited to movement difficulties. Many patients also experience mood disorders, cognitive decline, sleep disturbances, and digestive issues. One of the most puzzling aspects of the disease is that these non-motor symptoms often appear years before movement problems begin, hinting that the disease process may start outside the brain. Researchers have increasingly focused on alpha-synuclein, a protein that normally exists in neurons but can become misfolded and clump together into toxic aggregates. These protein clumps form structures called Lewy bodies, which are found in the brains of people with Parkinson’s and related disorders.

The idea that misfolded alpha-synuclein could spread from peripheral organs to the brain has gained traction over the past decade. For example, studies have shown that injecting these toxic protein aggregates into the gut of animals can lead to brain changes and movement impairments over time. The current study builds on that idea by turning attention to the kidneys, suggesting that they may be an overlooked origin point for this disease process—particularly in people with impaired kidney function.

The research team used a combination of human tissue samples and animal experiments. They examined kidney samples from patients with Parkinson’s disease or related disorders, as well as from people with end-stage kidney disease who had no known brain conditions. The researchers also used genetically modified mice, normal wild-type mice, and mice with kidney failure to test how alpha-synuclein behaves in the body under different conditions. In addition, they used surgical techniques and virus-based tracing to map nerve connections between the kidney and the brain.

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In their analysis of human samples, the researchers found that misfolded and phosphorylated alpha-synuclein was present in the kidneys of 10 out of 11 people who had Parkinson’s or dementia with Lewy bodies. This abnormal protein was mostly seen in nerve fibers near small blood vessels. Importantly, similar protein deposits were found in the kidneys of 17 out of 20 patients with chronic kidney disease, even though they had no signs of Parkinson’s or other neurological disorders during life. In some of these patients, early-stage alpha-synuclein pathology was also found in the spinal cord, midbrain, or amygdala—areas affected in Parkinson’s disease. This suggests that kidney disease may quietly set the stage for later brain involvement.

In mice, the researchers demonstrated that the kidneys play an active role in clearing alpha-synuclein from the blood. When they injected alpha-synuclein into healthy mice, the protein quickly accumulated in the kidneys and then disappeared, indicating efficient clearance. But in mice with kidney failure, the protein stuck around longer in the blood and built up in the kidneys. This impaired clearance was also seen in experiments with rabbits and in lab tests using human kidney tissue. The team found that kidney enzymes called cathepsins are largely responsible for breaking down alpha-synuclein, and these enzymes don’t work as well when the kidneys are damaged.

The buildup of alpha-synuclein in the kidneys turned out to have dangerous consequences. When researchers injected toxic alpha-synuclein fibrils directly into the bloodstream of mice with kidney failure, they saw the protein spread not just in the kidneys, but into the brain and spinal cord. This led to the appearance of Parkinson’s-like pathology in brain regions involved in movement and memory. Mice developed a loss of dopamine-producing neurons in the brain’s substantia nigra and showed clear motor problems, such as poor balance and abnormal walking patterns. None of this occurred in mice with healthy kidneys injected with the same protein.

To investigate how the protein spread from the kidney to the brain, the researchers injected alpha-synuclein fibrils directly into the kidneys of genetically modified mice. Over the following months, they observed the protein moving along known nerve pathways from the kidney to the spinal cord and then into various brain regions. Using viral tracers and surgical denervation to disrupt these pathways, they confirmed that the kidney-to-brain spread depended on intact nerve connections. Mice whose kidney nerves were cut did not develop brain pathology even after receiving direct kidney injections of toxic alpha-synuclein.

The researchers also tested whether blood cells might be contributing to the problem. Most of the alpha-synuclein in the blood is found in red blood cells, and patients with kidney disease often have fragile or damaged red cells. To see if removing blood-derived alpha-synuclein could prevent disease, the researchers used bone marrow transplants to replace the blood cells of genetically modified mice with those from alpha-synuclein knockout mice.

The result was a sharp drop in alpha-synuclein levels in the blood—and a significant reduction in brain pathology. These mice also retained more dopamine neurons and had fewer motor symptoms. However, this protective effect was only seen when the mice were not exposed to external sources of toxic alpha-synuclein. Once the fibrils were introduced directly, the disease process resumed, even in mice without blood-derived alpha-synuclein.

The findings suggest that the kidney may act as a gateway organ in the development of Lewy body diseases like Parkinson’s. When the kidney is working properly, it clears alpha-synuclein from the blood before it can do harm. But when kidney function is impaired, the protein can build up, deposit in the kidney itself, and travel to the brain via nerve pathways. This could help explain why people with chronic kidney disease have a higher risk of Parkinson’s disease.

There are some limitations to the study. Although the researchers identified a strong link between kidney dysfunction and the spread of alpha-synuclein, it remains unclear whether this pathway plays a role in all cases of Parkinson’s disease. Not everyone with kidney disease develops Parkinson’s, and not all Parkinson’s cases begin with peripheral involvement. Additionally, while the findings in mice were convincing, human biology is more complex. More research is needed to understand how the kidney–brain pathway operates in living people over time and to identify other potential routes of protein spread.

Future studies may explore whether targeting peripheral alpha-synuclein could help prevent or delay Parkinson’s disease. For example, drugs that enhance the kidney’s ability to break down the protein or therapies that block its transmission along nerves might offer new treatment avenues. Though kidney denervation or bone marrow transplants are unlikely to be used clinically, antibody-based therapies that remove circulating alpha-synuclein could be a more practical strategy.

The study, “Propagation of pathologic α-synuclein from kidney to brain may contribute to Parkinson’s disease,” was authored by Xin Yuan, Shuke Nie, Yingxu Yang, Congcong Liu, Danhao Xia, Lanxia Meng, Yue Xia, Hua Su, Chun Zhang, Lihong Bu, Min Deng, Keqiang Ye, Jing Xiong, Liam Chen, and Zhentao Zhang.