Study discovers Parkinson’s disease-linked protein impairs mitochondria

Mitochondria are organelles inside cells that carry out a mix of important tasks. These structures produce energy and help keep the cells’ interior environment in a state of healthy equilibrium, among other functions.

Study discovers Parkinson’s disease-linked protein impairs mitochondria
Unhealthy mitochondria are marked in a gradient from white to red, with white being the least healthy, in contrast to healthy mitochondria that appear in blue. This still image is from a microscope video showing mitochondria moving in a fruit fly larval neuron expressing elevated levels of the protein alpha-synuclein. Image Credit: T. J. Krzystek and Shermali Gunawardena.

Recently, researchers discovered that a protein linked with Parkinson’s disease can impair these cellular powerhouses. The results were derived from experiments where fruit fly larvae were genetically engineered to produce extremely high amounts of a protein, known as alpha-synuclein.

When fruit fly larvae expressed alpha-synuclein at elevated levels similar to what is seen in Parkinson’s disease, many of the mitochondria we observed became unhealthy, and many became fragmented. Through detailed experiments, we also showed that different parts of the alpha-synuclein protein seem to be responsible for these two problems and that fragmented mitochondria can actually be healthy.”

Shermali Gunawardena, PhD, Study Senior Author and Associate Professor, Biological Sciences, College of Arts and Sciences, University at Buffalo

This is a key finding because before, people thought fragmented mitochondria were unhealthy mitochondria,” adds Shermali Gunawardena.

The findings can be of great interest in the area of drug development, as abnormal aggregates of alpha-synuclein in brain cells are a characteristic of Parkinson’s disease, and mitochondrial damage is also seen in patients.

This research showcases the advantage of using fruit fly larvae as a model organism to study how neurons become damaged during devastating diseases such as Parkinson’s disease. Through this approach, we pieced together a new understanding for how the Parkinson’s disease-related protein alpha-synuclein disrupts the health and movement of mitochondria—the epicenter for energy production in cells.”

Thomas J. Krzystek, Study Co-First Author and PhD Candidate, Biological Sciences, University at Buffalo

Krzystek further states, “We believe this work emphasizes a promising path that can be explored for potential therapeutics aimed at improving mitochondrial health in Parkinson’s disease patients.”

The research was published on August 17th, 2021, in the Cell Death & Disease journal. The co-first authors of the study are Krzystek and Rupkatha Banerjee, Ph.D., a postdoctoral research associate at Scripps Research who completed her doctorate in biological sciences at UB. Gunawardena is the senior author of the study. The study was a joint effort, with many members of the Gunawardena lab making major contributions.

Along with Banerjee, Gunawardena, and Krzystek, the paper’s authors include undergraduates Layne Thurston, JianQiao Huang, and Saad Navid Rahman, and Ph.D. student Kelsey Swinter, from the UB Department of Biological Sciences, and Tomas L. Falzone at the Universidad de Buenos Aires and Instituto de Investigación en Biomedicina de Buenos Aires.

A detailed look at alpha-synuclein and mitochondria

By conducting tests in fruit fly larvae, the researchers were able to sort out intricate details on interactions between alpha-synuclein and mitochondria.

For instance, the research not only concludes that various sections of the alpha-synuclein protein are most likely responsible for inducing mitochondrial fragmentation and damaging mitochondrial health; the study also pinpoints these sections and elaborates how other proteins might interact with them to drive these changes.

More precisely, the proteins PINK1 and Parkin—both related to Parkinson’s disease—might interact with one end of alpha-synuclein to influence mitochondrial health, while a protein named DRP1 might interact with the other end to break mitochondria, state the researchers.

Mitochondrial impairments have long been linked to the pathogenesis of Parkinson’s disease. However, the role of alpha-synuclein in mitochondrial quality control so far has not been comprehensively investigated.”

Rupkatha Banerjee, Study Co-First Author and Postdoctoral Research Associate, Scripps Research

Our study unravels the intricate molecular mechanisms by which the different regions of alpha-synuclein exert distinct effects on mitochondrial health, bringing into light a potential pathway that could be targeted for exploring new therapeutic interventions in Parkinson’s disease,” added Banerjee.

We were able to tease out specific mechanistic functions for alpha-synuclein by using imaging tools and a color-tagged marking system to observe the process of what happens to mitochondria when alpha-synuclein is elevated. This system allowed us to observe the health, size, and the movement behaviors of mitochondria at the same time in living neurons in a whole organism,” explains Gunawardena.

Source:
Journal reference:

Krzystek, T. J., et al. (2021) Differential mitochondrial roles for α-synuclein in DRP1-dependent fission and PINK1/Parkin-mediated oxidation. Cell Death & Disease. doi.org/10.1038/s41419-021-04046-3.

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