Summary: Irisin, a hormone secreted into the blood during aerobic and high-endurance exercise, reduces alpha-synuclein levels and restores movement in mouse models of Parkinson’s disease.
Font: Johns Hopkins Medicine
Researchers from Johns Hopkins Medicine and the Dana Farber Cancer Institute in Boston have shown that a hormone secreted into the blood during endurance or aerobic exercise reduces levels of a protein linked to Parkinson’s disease and stops movement problems in mice.
Parkinson’s disease, a neurological condition that causes people to lose control of their muscles and movements, affects about 1 million people in the US.
If confirmed in further laboratory research and clinical trials, the researchers’ study in mice engineered to have symptoms of Parkinson’s disease could pave the way for an irisin hormone-based Parkinson’s disease therapy.
The results of the researchers’ tests appeared on August 31 in Proceedings of the National Academy of Sciences.
Ted Dawson, MD, Ph.D., of Johns Hopkins Medicine, and Bruce Spiegelman, Ph.D., of Dana Farber, worked together to investigate the link between the exercise molecule irisin and Parkinson’s disease.
For unknown reasons, resistance exercise has long been found to relieve symptoms of Parkinson’s disease. Dawson, whose research focuses on neurodegenerative diseases, including Parkinson’s disease, said one of the first clues about the link between exercise, Parkinson’s disease and irisin came from Spiegelman, whose first paper on irisin was published in 2012 in Nature and later in other scientific journals, showing that a protein called irisin peptide is released into the blood and increases with resistance exercise.
In the last decade, other labs have found that exercise raises irisin levels, and there is interest in investigating the connection between irisin and Alzheimer’s disease, as well as Parkinson’s disease.
To test irisin’s effects on Parkinson’s disease, Dawson and Spiegelman’s teams began with a research model used by Dawson in which mouse brain cells are modified to propagate small, thin fibers of alpha synuclein, a protein that regulates moods and movements related to the brain. neurotransmitter dopamine.
When alpha synuclein proteins clump together, those clumps kill dopamine-producing brain cells, a key trigger of Parkinson’s disease. The alpha synuclein fibrous clumps are very similar, says Dawson, to those found in the brains of people with Parkinson’s disease.
In the laboratory model, the researchers found that irisin prevented the accumulation of alpha-synuclein clusters and associated brain cell death.
Next, the research teams tested the effects of irisin in mice engineered to have Parkinson-like symptoms. They injected alpha synuclein into an area of the mouse brain, called the striatum, where dopamine-producing neurons extend.
Two weeks later, the researchers injected the mice with a viral vector that increased blood levels of irisin, which can cross the blood-brain barrier.
Six months later, the mice given irisin had no muscle movement deficits, while those given a placebo showed deficits in grip strength and their ability to descend a pole.
Additional brain cell studies among the mice given irisin showed that the exercise hormone reduced levels of the Parkinson’s disease-related alpha synuclein by 50% to 80%. The research team showed that irisin also speeds up the transport and breakdown of alpha-synuclein through fluid-filled sacs called lysosomes in brain cells.
“If irisin’s utility works, we could envision it developing into a recombinant protein or gene therapy,” says Dawson, referring to the expanding field of drug development targeting the use of cellular genetics to treat disease. Dawson is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases, professor of neurology, and director of the Johns Hopkins Institute for Cell Engineering.
“Since irisin is a naturally occurring peptide hormone and appears to have evolved to cross the blood-brain barrier, we believe irisin is worth further evaluation as a potential therapy for Parkinson’s and other forms of neurodegeneration,” adds Spiegelman.
Dawson and Spiegelman have applied for patents on the use of irisin in Parkinson’s disease. Spiegelman has created a biotech company, Boston-based Aevum Therapeutics Inc., to turn irisin into treatments for neurodegenerative diseases.
Other scientists who contributed to the research include Tae-In Kam, Hyejin Park, Shih-Ching Chou, Yu Ree Choi, Devanik Biswas, Justin Wang, Yu Shin, Alexis Loder, Senthilkumar Karuppagounder, and Valina Dawson at Johns Hopkins, and Jonathan Van Vranken. , Melanie Mittenbuhler, Hyeonwoo Kim, Mu A, and Christiane Wrann at Harvard Medical School.
See also
Money: The research was funded by the JPB Foundation, the Maryland Stem Cell Research Fund, the Mark Foundation for Cancer Research, the Damon Runyon Cancer Research Foundation, and the Deutsche Forschungsgemeinschaft.
About this Parkinson’s disease research news
Author: vanessa wasta
Font: Johns Hopkins Medicine
Contact: Vanessa Wasta – Johns Hopkins Medicine
Image: The image is in the public domain.
original research: Open access.
“Amelioration of α-synuclein-induced pathological Parkinson’s disease by irisin” by Ted Dawson et al. PNAS
Summary
Amelioration of α-synuclein-induced pathological Parkinson’s disease by irisin
Physical activity provides clinical benefit in Parkinson’s disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents α-synuclein (α-syn)-induced pathological neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD.
Intravenous administration of irisin via viral vectors after stereotaxic intrastriatal injection of α-syn PFF caused a reduction in pathological α-syn formation and prevented dopaminergic neuron loss and striatal dopamine decline. Irisin also substantially reduced α-syn PFF-induced motor deficits as behaviorally assessed by the grip and barbell strength test.
Sustained recombinant irisin treatment of primary cortical neurons attenuated PFF α-syn toxicity by reducing α-syn phosphorylated serine 129 formation and neuronal cell death. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathological α-syn by enhancing endolysosomal degradation of pathological α-syn.
Our findings highlight the potential for therapeutic disease modification of irisin in PD.
