Researchers discover that an inhibitory protein destroys toxic agglomerates in Parkinson's disease

Newswise – WASHINGTON – A Parkinson's disease is characterized by clusters of alpha-synuclein protein 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 demonstrated how to stop the accumulation and decomposition of tufts – until now perhaps.

A team of neurologists at Georgetown University Medical Center (GUMC) has discovered through studies on mice and human brains that one of the reasons why Lewy bodies are growing is that a molecule, USP13, has removed all the "tags" placed on 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 inhibition of USP13 in murine models of Parkinson's disease removes both Lewy bodies and prevents them from replenishing. The "tag" that the USP13 removes is called ubiquitin, which marks the breakdown of alpha-synuclein.

"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 post mortem autopsies of people who donated their brains to researchers, including 11 people with Parkinson's disease and a control group of 9 people without Parkinson's. 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 was never discovered before this work. Its presence indicates that this molecule could reduce parkin 's ability to label proteins with ubiquitin or could remove ubiquitin from certain molecules such as alpha – synuclein, which would result in an accumulation of toxic tufts in the brain, "said Charbel Moussa, MBBS, PhD, said the high-level study. researcher and director of the GUMC translational neurotherapeutic program.

Studies on murine models of Parkinson's disease have shown that inactivation of the USP13 gene increases 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 treatment study in people with Parkinson's disease, nilotinib, worked better with USP13 inhibition. Nilotinib is approved by the FDA for use in specific blood cancers.

"Our discovery clearly indicates that USP13 inhibition 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 the treatment of Parkinson's disease and other neurodegenerative diseases."

"To our knowledge, these data are the first to elucidate the role of USP13 in neurodegeneration," says Liu, suggesting that other neurodegeneration disorders with protein clusters, such as Alzheimer's disease, 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 Jesuit Catholic principle of cura personalis – 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).