Alpha-synuclein clumps may form in kidneys before traveling to brain
Findings help explain link between chronic kidney disease, Parkinson's risk
People with chronic kidney disease, a condition characterized by a progressive loss of kidney function, have alpha-synuclein protein deposits in their kidneys, a study in China has found.
Alpha-synuclein is a key marker of Parkinson’s disease, suggesting a possible link between kidney function and the neurodegenerative condition.
“These findings are in line with previous reports that [chronic kidney disease] is associated with an increased risk of idiopathic [of unknown cause] PD [Parkinson’s disease],” researchers wrote in “Propagation of pathologic [alpha]-synuclein from kidney to brain may contribute to Parkinson’s disease,” which was published in Nature Neuroscience.
In Parkinson’s, misfolded alpha-synuclein aggregates into toxic clumps called Lewy bodies. These clumps can form in organs outside the brain, such as the gut, and then travel to the brain, where they cause damage to nerve cells. Additionally, alpha-synuclein is present at high levels in red blood cells.
Kidney problems appear to increase risk of neurodegenerative diseases
Kidney problems appear to increase the risk of developing neurodegenerative diseases like Parkinson’s, but the mechanisms behind this connection are not clear. To know more, the researchers checked for the presence of pS129, a faulty version of alpha-synuclein that tends to misfold and form clumps, in the postmortem kidneys from people diagnosed with Parkinson’s and dementia with Lewy bodies (DLB), a form of dementia that is characterized by toxic clumps of alpha-synuclein protein in the brain and whose symptoms partially overlap with those of Parkinson’s.
Of 11 patients, eight had been diagnosed with Parkinson’s and three with DLB. Ten had evidence of pS129 deposits in samples of their kidneys, especially in nerve fibers close to small blood vessels.
The study also included samples from 20 patients with chronic kidney disease and 17 individuals who were not diagnosed with a neurological disorder or kidney disease (controls). Of 20 patients, 17 tested positive for pS129 deposits in the kidneys. All the control samples were negative.
For seven patients diagnosed with chronic kidney disease with postmortem samples available, pS129 deposits were present in the central nervous system (CNS, comprising the brain and spinal cord), which suggests alpha-synuclein may form toxic clumps in the kidneys before it reaches the CNS.
All patients with chronic kidney disease tested had evidence of disease-causing alpha-synuclein in their kidneys despite a lack of history of Lewy body disease, which indicates these were most likely presymptomatic deposition of disease-causing alpha-synuclein, the researchers wrote.
The kidneys play an essential role in protein metabolism, the process by which the body breaks down and uses proteins for various functions. To investigate if the kidneys remove alpha-synuclein protein from circulation, the researchers injected alpha-synuclein into mice to study its clearance through the kidneys.
Alpha-synuclein found to accumulate in kidneys 30 minutes after injection
Intravenous, or into-the-vein, injection of alpha-synuclein revealed the protein was quickly degraded in the blood, with only a small portion excreted through urine. In animals with renal failure, however, there was an impaired blood clearance of the protein. Thirty minutes after the injection, alpha-synuclein was found to accumulate mainly in the kidneys, but not the heart, liver, spleen, lung, brain, small intestine, or colon.
“These findings indicate that the kidneys physiologically remove [alpha-synuclein] from the blood and that this function is compromised in patients with CKD,” the researchers wrote.
When alpha-synuclein was injected directly into the kidneys, it was found to spread into the brain and induce Parkinson’s-like motor deficits.
However, severing the nerve fibers connecting the kidneys and brain prevented alpha-synuclein from reaching the brain. Additionally, in mice genetically engineered to lack alpha-synuclein in their blood cells, the spread of alpha-synuclein was reduced.
“Removal of [alpha-synuclein] from the blood may hinder the progression of [Parkinson’s], providing new strategies for therapeutic management of [Lewy body disease],” the researchers concluded, noting practical approaches in clinical settings have yet to be developed.
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