Immune cells known as “natural killer” (NK) cells appear to fight the cellular changes that lead to conditions such as Parkinson’s disease. Understanding how they do this may lead to new therapies for the neurodegenerative disorder, according to a study from the University of Georgia.
The study, “NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy,” was published in the journal Proceedings of the National Academy of Sciences.
In Parkinson’s, patients progressively lose motor control and, to some degree, cognitive functions. One of the key clinical findings in Parkinson’s is the presence of insoluble clumps, or aggregates, of a protein called alpha-synuclein.
Alpha-synuclein is mainly found within the central nervous system (CNS), which is comprised of the brain and spinal cord. The clumps that build up in the brain are associated with the death of dopamine-producing (dopaminergic) neurons that lead to the disease’s symptoms.
They are one of the primary therapeutic targets among all Parkinson’s treatments. The discovery that the immune system can target these clumps on its own raises the possibility of designing better therapies based on the body’s own natural defenses.
Natural killer cells are a type of white blood cells that form the immune system’s first line of defense. They constantly patrol the body, attacking and destroying foreign bodies such as viruses and invading bacteria, as well as harmful native cells such as tumor cells.
Beginning with the observations that NK cells have been found to play a protective role in the CNS and that they are elevated in the blood of Parkinson’s patients, the UGA researchers sought to investigate their potential role in the disease.
Using mice, they looked closer at the relationship between NK cells and alpha-synuclein and experimented with the effect of removing NK cells in a mouse model of Parkinson’s.
As in human Parkinson’s patients, the researchers found natural killer cells in the brains of mice. There, these cells homed in on alpha-synuclein aggregates and showed evidence that they could absorb and degrade them. Importantly, the alpha-synuclein clumps reduced the NK cells’ cytotoxicity, with the killer cells releasing less of the pro-inflammatory — or inflammation-promoting — cytokine interferon-gamma, which is critical to both innate and adaptive immunity. Cytokines are small proteins released by immune cells that act upon other cells and have a specific effect on the interactions and communications between them.
Depleting NK cells in the mouse model caused Parkinson’s-like symptoms to progressively worsen, suggesting that natural killer cells did, in fact, exert a protective effect within the CNS of the mice.
Alongside the worsening of symptoms, the researchers observed that without the NK cells present, alpha-synuclein aggregates grew enlarged inside the mouse brains.
Interestingly, the depletion of natural killer cells in mice led to the death of dopaminergic neurons in the striatum of the brain, but not in the substantia nigra, where it usually occurs in humans. The striatum is a brain region responsible for the control of voluntary movement, while the susbtantia nigra contains a large percentage of all dopamine-producing neurons.
The study’s researchers point out that these results are preliminary and warrant more investigation into the role of NK cells in Parkinson’s disease.
“Our data suggest that NK cells have the potential to become the basis of a cell-therapeutic strategy to stop or slow abnormal protein pathogenesis in [Parkinson’s] and possibly other synuclein-related neurodegenerative diseases,” the researchers said.
Future steps will involve examining how natural killer cell function changes with age.
“Our preliminary data suggest that the number and function of NK cells are decreased in aged animals, and display impaired ability to perform their normal functions,” Jae-Kyung Lee, the study’s lead author, said in a press release.
“We would like to look deeper at age-related changes associated with NK cell biology and the wider implications for the health and well-being of older adults,” Lee said.
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