Scientists examine how a protein linked to Parkinson’s disease attacks a cell’s power plants

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Inside cells, organelles called mitochondria perform a mix of vital tasks. These structures generate energy and help keep the internal environment of cells in a healthy state of balance, among other functions.

Now scientists are showing how a protein associated with Parkinson’s disease can damage these cell powerhouses.

The results come from experiments in which fruit fly larvae were genetically engineered to produce unusually high amounts of the protein, called alpha-synuclein.

“When fruit fly larvae expressed alpha-synuclein at high levels similar to those seen in Parkinson’s disease, many of the mitochondria we observed became unhealthy and many became fragmented. Through detailed experiments, we have also shown that different parts of the alpha-synuclein protein appear to be responsible for these two problems, and that fragmented mitochondria may in fact be healthy. This is a key finding because people used to think fragmented mitochondria were unhealthy mitochondria, ”says Shermali Gunawardena, associate professor of biological sciences, College of Arts and Sciences.

The results could be of interest in the context of drug development, as abnormal aggregates of alpha-synuclein in brain cells are a hallmark of Parkinson’s disease, and mitochondrial damage has also been observed in patients.

“This research shows the benefit of using fruit fly larvae as a model organism to study how neurons are damaged in devastating diseases such as Parkinson’s disease,” says TJ Krzystek, PhD student in Biological Sciences at UB . “Through this approach, we have gained a better understanding of how alpha-synuclein, a protein linked to Parkinson’s disease, disrupts the health and movement of mitochondria, the epicenter of energy production in cells. We believe this work highlights a promising avenue that can be explored for potential therapies aimed at improving mitochondrial health in patients with Parkinson’s disease.

The study was published August 17 in the journal Cell Death and Disease.

Co-first authors are Krzystek and Rupkatha Banerjee, a postdoctoral research associate at Scripps Research who completed her doctorate in biological sciences at UB. Gunawardena is the main author.

The research was a collaborative effort, with many members of the Gunawardena lab making important contributions. In addition to Banerjee, Gunawardena and Krzystek, the authors of the article include undergraduates Layne Thurston, JianQiao Huang, and Saad Navid Rahman, and doctoral student Kelsey Swinter, all in the Department of Biological Sciences at UB , and Tomas L. Falzone at the University of Buenos Aires. and Instituto de Investigación en Biomedicina de Buenos Aires.

Through tests on fruit fly larvae, scientists were able to uncover intricate details about the interactions between alpha-synuclein and mitochondria.

For example, the study not only concludes that different sections of the alpha-synuclein protein are likely responsible for mitochondrial fragmentation and the deterioration of mitochondrial health; the research also identifies these sections and describes how other proteins can interact with them to cause these changes. Specifically, the PINK1 and Parkin proteins – both linked to Parkinson’s disease – can interact with one end of alpha-synuclein to influence mitochondrial health, while a protein called DRP1 can interact with the other end to break down mitochondria, according to scientists.

“Mitochondrial deficiencies have long been linked to the pathogenesis of Parkinson’s disease,” Banerjee explains. “However, the role of alpha-synuclein in mitochondrial quality control has not yet been fully investigated. Our study uncovers the complex molecular mechanisms by which different regions of alpha-synuclein exert effects. distinct studies on mitochondrial health, highlighting a potential pathway that could be targeted to explore novel therapeutic interventions in Parkinson’s disease.

“We were able to discover specific mechanical functions for alpha synuclein using imaging tools and a color labeling system to observe the process of what happens to mitochondria when alpha synuclein is elevated,” Gunawardena adds. . “This system has allowed us to observe the health, size and movement behaviors of mitochondria at the same time in living neurons of an entire organism.”


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