How a Parkinson's disease-linked protein attacks a cell's powerhouses
Scientists explore how alpha-synuclein impacts the health of
mitochondria, organelles that produce most of a cell's energy

Date:
August 18, 2021
Source:
University at Buffalo
Summary:
Inside cells, organelles called mitochondria carry out a medley of
vital tasks. These structures generate energy and help to keep the
cells' interior environment in a state of healthy equilibrium, among
other functions. Now, scientists show in detail how alpha-synuclein,
a protein associated with Parkinson's disease, can damage these
cellular powerhouses.



FULL STORY ========================================================================== Inside cells, organelles called mitochondria carry out a medley of
vital tasks.

These structures generate energy and help to keep the cells' interior environment in a state of healthy equilibrium, among other functions.


==========================================================================
Now, scientists show how a protein associated with Parkinson's disease
can damage these cellular powerhouses.

The findings 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 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. This is a
key finding, because before, people thought fragmented mitochondria
were unhealthy mitochondria," says Shermali Gunawardena, PhD, associate professor of biological sciences in the University at Buffalo 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 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," says TJ Krzystek, UB PhD candidate
in biological sciences. "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.

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 study was published on Aug. 17 in
the journal Cell Death and Disease.



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

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

A detailed look at alpha-synuclein and mitochondria Through tests in
fruit fly larvae, the scientists were able to tease out intricate details regarding 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 causing mitochondrial fragmentation and damaging mitochondrial health; the research also
identifies these sections and describes how other proteins may interact
with them to drive these changes. More specifically, the proteins PINK1
and Parkin -- both linked to Parkinson's disease -- may interact with
one end of alpha-synuclein to influence mitochondrial health, while a
protein called DRP1 may interact with the other end to break mitochondria, scientists say.

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

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." "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," Gunawardena adds. "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." ========================================================================== Story Source: Materials provided by University_at_Buffalo. Original
written by Charlotte Hsu.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Thomas J. Krzystek, Rupkatha Banerjee, Layne Thurston, JianQiao
Huang,
Kelsey Swinter, Saad Navid Rahman, Tomas L. Falzone, Shermali
Gunawardena. Differential mitochondrial roles for a-synuclein in
DRP1- dependent fission and PINK1/Parkin-mediated oxidation. Cell
Death & Disease, 2021; 12 (9) DOI: 10.1038/s41419-021-04046-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210818130512.htm

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