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WASHINGTON – Parkinson's disease is characterized by clusters of alpha-synuclein proteins that accumulate in the motor control zone of the brain and destroy the dopamine-producing neurons. Natural processes can not erase these clusters, called Lewy bodies, and no one has shown how to stop the accumulation as well as the clumping decomposition – until perhaps now.
A team of neurologists at the Georgetown University Medical Center (GUMC) has discovered, through studies on mice and human brains, that one of the reasons Lewy bodies are developing is that a molecule , USP13, has removed all the "tags" placed on the alpha-synuclein that tag the protein for destruction. Toxic piles of alpha-synuclein accumulate and are never removed.
The results, published in Human molecular genetics, show that the inhibition of USP13 in murine models of Parkinson's disease eliminated both Lewy bodies and prevented them from restoring themselves. The "tag" that USP13 removes is called ubiquitin, which marks alpha-synuclein for the purpose of its degradation.
"This study provides new evidence that USP13 affects the development and clearance of Lewy body protein clusters, suggesting that USP13 targeting could be a therapeutic target for Parkinson's disease and Other similar forms of neurodegeneration, "says Xiaoguang Liu, MD, Ph.D., principal investigator of the study. , assistant professor of neurology.
There are three forms of motor disorders associated with the accumulation of alpha-synuclein. These "synucleinopathies" include Parkinson's disease, Lewy body dementia and multisystemic atrophy.
Parkin belongs to the family of ubiquitin ligase enzymes. Ubiquitination is a process in which molecules are labeled (or labeled) with ubiquitin and directed to cellular machines that break them down. USP13 is known as a desubiquitination enzyme, which eliminates ubiquitin labels from proteins. USP13 renders parkin ineffective by eliminating ubiquitin (desubiquitination) protein labels. Loss of parkin function leads to genetically inherited forms of Parkinson's disease.
The study began with postmortem autopsies of people who donated their brains to research, including eleven Parkinson's disease patients and a nine-day control group without Parkinson's disease. Autopsies, which occurred 4 to 12 hours after death, showed that the USP13 level was significantly increased in the average brain of patients with Parkinson's disease compared to control participants.
"The overexpression of USP13 in post-mortem brains with Parkinson's disease had never been discovered before this work, and its presence indicates that this molecule could reduce parkin's ability to label proteins with high blood pressure." 39 ubiquitin or could ubiquitin remove certain molecules such as alpha-synuclein, resulting in accumulation of toxic clusters in the brain, "said Charbel Moussa, MBBS, PhD, lead researcher of the study and Director of the GUMC Translational Neurotherapeutic Program.
Studies on murine models of Parkinson's disease then demonstrated that inactivation of the USP13 gene increased the ubiquitination and destruction of alpha-synuclein. The researchers also found that the inactivation of USP13 protected mice against the death of dopaminergic neurons induced by alpha-synuclein. The mice had improved motor performance; Parkin protein was increased and alpha-synuclein was eliminated.
The researchers also found that a more recent study treatment in patients with Parkinson's disease, nilotinib, worked best when USP13 was inhibited. Nilotinib is approved by the FDA for use in specific blood cancers.
"Our discovery clearly indicates that the inhibition of USP13 is a strategic step to activate parkin and combat the desubiquitination of alpha-synuclein, in order to increase the clearance of toxic proteins," added Moussa. "Our next step is to develop a small molecular inhibitor, USP13, to be used in combination with nilotinib to maximize protein clearance in Parkinson's disease and other neurodegenerative diseases."
"To our knowledge, these data are the first to elucidate the role of USP13 in neurodegeneration," Liu said, suggesting that other neurodegenerative disorders with protein clumps, such as the disease of Alzheimer's, could have a similar pathology.
"The clearance of neurotoxic proteins, including alpha-synuclein, may depend on the balance between ubiquitination and deubiquitination," she says.
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Associate researchers include Michaeline Hebron, MS, Wangke Shi and Irina Lonskaya, Ph.D., both from the Department of Neurology and the Georgetown University Medical Center.
Georgetown University has a patent (US Patent 9,393,244) relating to the technology described in this manuscript, on which Moussa is named inventor.
These studies were funded by grants awarded to Moussa by the Michael J. Fox Foundation and Emerald Foundation, Inc.
About Georgetown University Medical Center
The Georgetown University Medical Center (GUMC) is a world-class academic medical center with a three-part mission: research, education and patient care (through MedStar Health). The mission of GUMC is implemented with a strong emphasis on public service and dedication to the catholic cura personalis Jesuit principle – or "care of the whole person". The medical center includes the School of Medicine and the School of Nursing and Health, both of which are nationally classified; Georgetown Lombardi Comprehensive Cancer Center, designated as a global cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which represents the majority of externally funded research at GUMC, including a National Institutes of Health Clinical and Translational Science Award. Connect with GUMC on Facebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@GeorgetownMedicine).
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