Genetic program protects neurons from degeneration
Study finds genes in fruit flies that are presumed to have a similar
function in humans

Date:
August 13, 2021
Source:
University of Bonn
Summary:
Researchers have identified a previously unknown genetic program
in the fruit fly. The genetic material involved controls the
development of the neurons while also protecting them from
degeneration. They have hardly changed in the course of evolution
over hundreds of millions of years and also exist in a comparable
form in humans. Initial data show that they presumably perform
similar tasks there. The results may therefore also provide a
starting point for new active ingredients for neurodegenerative
diseases.



FULL STORY ========================================================================== Researchers at the University of Bonn (Germany) have identified a
previously unknown genetic program in the fruit fly. The genetic
material involved controls the development of the neurons while also
protecting them from degeneration. They have hardly changed in the course
of evolution over hundreds of millions of years and also exist in a
comparable form in humans. Initial data show that they presumably perform similar tasks there. The results may therefore also provide a starting
point for new active ingredients for neurodegenerative diseases. They
are published in the journal Neuron.


==========================================================================
A fruit fly's brain is barely larger than the dot on this i, yet
nevertheless consists of around 100,000 neurons. There are almost
a million times as many neurons in the human brain. And the other
differences between the two thinking organs are also considerable --
after all, the paths of Drosophila melanogaster (as the species is
known by its scientific name) and Homo sapiens separated several hundred millions of years ago during evolution.

There are nevertheless astounding parallels between the two organisms. The current study has now discovered another of them. The research group led
by Prof. Dietmar Schmucker from the LIMES Institute at the University
of Bonn investigated what function certain genetic material in the
fruit fly plays in the development of its brain. "We specifically
switched off individual genes and observed how the neurons changed as
a result," explains Schmucker, who is holding a Humboldt Professorship
in Bonn since 2019. "During this, we came upon a gene called WNK, which performs an incredible dual role." WNK performs a dual role The crucial discovery was made by the lead author of the study, Dr. Azadeh Izadifar,
a postdoctoral student in Schmucker's working group. She was able to show
that WNK is necessary for connecting the neurons during the development
of the nervous system. If the gene is not present, for instance, due
to an experimentally induced mutation, then the branching of the axons
does not take place. These axons are cable-like cell offshoots that
transmit electrical signals to other neurons. They are usually connected
to many different receptor cells via synapses. "Without the WNK protein, functional axonal branches are largely absent," emphasizes Izadifar.

In adult animals, however, WNK appears to protect existing axons. If
the genetic material is switched off at this late time, the branches
degenerate in the adult animals. "Both functions may be two sides of the
same coin," presumes Schmucker. This is because WNK appears to be part of
a regulatory network that controls both the formation during development
and also the degeneration of neuron connections in adult animals. The
gene contains the blueprint for what is known as a kinase. This refers
to an enzyme that "glues" certain chemical components to other proteins,
thus controlling their activity. The WNK kinase regulates and supports
a factor called NMNAT, which protects the neurons. At the same time, it inhibits at least two other proteins called Sarm and Axed. It is known
that they both play an important role in the active neurodegeneration
of axons.

Important balance between protection and degeneration However, the kinase
may not be directly involved in these opposing processes.

It fine-tunes an as-yet-unknown parameter and thus adjusts the balance
between protection and degeneration. Both processes are essential for
the function of the brain.

These results may offer new impetus for the understanding of how neurodegenerative diseases occur in humans and how they could possibly
be treated. This is because WNK kinases also exist in mammals -- in
mice as well as in us. Not only that, they also appear to be essential
for protecting our neurons, too. The results of a collaboration with
the research group led by Prof. Franck Polleux at Columbia University
in New York at least point in this direction. The team was able to show
that WNK kinases are also important for the formation of axonal branches
in mice and that their loss leads to the degeneration of axons. "It is
also known that certain WNK mutations in humans lead to nerve damage,
called peripheral neuropathy, which is accompanied by progressive sensory disorders in the arms and legs," explains Schmucker.

Schmucker hopes that the WNK kinase may perhaps be of therapeutic use
in the fight against neurodegenerative diseases -- such as by being overactivated using an active ingredient, thus increasing its ability
to protect neurons. The study also demonstrates the far-reaching
insights that can be gained from simple organisms such as the fruit
fly. Schmucker's research group is now using a second model system --
the western clawed frog Xenopus tropicalis. As a vertebrate, it is more
similar to humans than the fly is. Xenopus tadpoles are also more or less transparent. The effects of certain genetic manipulations on growth and degeneration of neurons can thus be observed in the living animal.

The study was supported with funding from the Belgian "Research Foundation
- - Flanders" (FWO), the Fondation pour la Recherche Medicale (FRM)
in France, the European Union as part of its ERC Starting Grants, and
by the Humboldt Foundation, the Roger De Spoelberch Fondation, and the
Thompson Family Foundation Initiative. Alongside the University of Bonn,
KU Leuven, the Universite' de Lyon, Columbia University New York, and
the University of Tokyo were involved in the work.

========================================================================== Story Source: Materials provided by University_of_Bonn. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Azadeh Izadifar, Julien Courchet, Daniel M. Virga, Tine Verreet,
Stevie
Hamilton, Derya Ayaz, Anke Misbaer, Sofie Vandenbogaerde, Laloe
Monteiro, Milan Petrovic, Sonja Sachse, Bing Yan, Maria-Luise
Erfurth, Dan Dascenco, Yoshiaki Kise, Jiekun Yan, Gabriela
Edwards-Faret, Tommy Lewis, Franck Polleux, Dietmar Schmucker. Axon
morphogenesis and maintenance require an evolutionary conserved
safeguard function of Wnk kinases antagonizing Sarm and
Axed. Neuron, 2021; DOI: 10.1016/ j.neuron.2021.07.006 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210813100326.htm

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