According to the Global Burden of Disease study, 6.2 million patients live with Parkinson’s disease (PD) and this number is expected to double by 2040. Although promising medications, such as levadopa, have been introduced, there are currently no cures for PD. Researchers at the University of Georgia are trying to change that with their recent discovery of how specialized immune cells in our bodies, known as natural killer cells, operate to fight the protein clumping that is a hallmark of PD.
Natural killer, or NK, cells were identified in the mid-1970s. Scientists eventually classified them as white blood cells, similar to T cells and yet also unique. T cells have receptors on their surface that enable them to recognize virally infected or cancerous cells and destroy them. NK cells are similar except that they have a much broader range of receptors, which helps them to recognize stressed cells infected by a host of viral, bacterial, and parasitic pathogens. They do not attack invading organisms directly but instead destroy the infected cells by binding to them and releasing cytotoxic chemicals.
Hypotheses have emerged that natural killer cells might be able to scavenge other types of stressed cells. For example, in PD, dopamine-producing (dopaminergic) neurons are destroyed by proteins known as alpha-synuclein (α-synuclein or α-syn) proteins. The α-synuclein accumulates until it forms large deposits, known as Lewy bodies, in cells located in the substantia nigra part of the brain. The presence of Lewy bodies is a clear biomarker of synucleinopathies, including Lewy body dementia and PD.
Evidence of Parkinson’s Prevention
The role of NK cells in the disruption of α-synuclein accumulation had never been explored until this new research conducted at the University of Georgia’s Regenerative Bioscience Center and reported in the journal Proceedings of the National Academy of Sciences. Using in vitro and in vivo studies of human patients and a mouse model, researchers found evidence that NK cells may be critical for regulating and restraining inflammation of brain tissue and protein clumping. Here are the key findings:
- NK cells are present in the brains of humans and mice with α-syn pathology. Researchers confirmed this by studying brain samples of both PD patients and age-matched controls. Looking for high levels of staining indicative of the presence of a unique NK cell marker, they found that 8 out of 11 synucleinopathy patient samples revealed positive staining. Next, researchers detected NK cell presence in the adult mouse brain, with the number of NK cells increasing with synuclein pathology.
- NK cells clear extracellular α-syn without any apparent activation. Researchers studied this by mixing NK cells with various concentrations of α-syn aggregates and using immunoblot analyses to measure how much α-syn became internalized by the NK cells. They observed that NK cells efficiently internalized various sizes of α-syn protein in a dose-dependent manner.
- Depletion of NK cells in a mouse model led to increased motor deficits, suggesting a protective role of NK cells in PD and other related neurodegenerative diseases. To determine the role of NK cells in vivo, researchers injected mice with an anti-NK monoclonal antibody. This depleted the number of NK cells found in the brain, spleen and inguinal lymph nodes. They then inoculated the animals with α-syn polymer and began observing for cognitive or postural abnormalities.As early as three weeks, treated mice began showing deficits in hind limb clasping. By 10 weeks, the animals were displaying more obvious clinical signs of PD, such as unstable gait and hunched posture. When brain samples of treated mice were examined, researchers observed higher numbers of α-syn inclusions (Lewy bodies) within the striatum, the pars compacta region of the substantia nigra and the brainstem.
A Future Immunotherapy
While still early, this research makes a promising case for the role of NK cells in disrupting or even preventing the onset of PD. NK cells may be able to both reduce inflammation in the brain and clear proteins that misfold and create the α-syn inclusions that are so toxic. NK cells may also play a role in cell signaling that boosts a larger immune response.
Either way, this research may be a first step toward an immunotherapy for PD patients. Given the global incidence and projected future prevalence of PD, such a novel treatment would have significant socioeconomic impact, reducing the burden on patients, their caregivers and the healthcare system.
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