Flawed quality control in the brain
New mouse type reveals when neurons fail to cope with misfolded proteins


Date:
August 19, 2021
Source:
Max-Planck-Gesellschaft
Summary:
Proteins are the 'tools' of our cells - they are essential to
all vital tasks. However, they are only able to do their jobs
if they fold correctly and adopt their respective, very specific
3D structure. To ensure that nothing goes wrong with the folding
process, it is strictly monitored in the cell. The consequences
of a flawed quality control can be seen, for example, in the
deposition of misfolded proteins in neurodegenerative diseases
such as Alzheimer's. Researchers have now developed a mouse line
that makes the state of protein balance visible in the mammalian
brain for the first time. In this way, the processes of protein
quality control can now be studied in healthy and diseased neurons
in more detail.



FULL STORY ========================================================================== Proteins are the "tools" of our cells -- they are essential to all
vital tasks.

However, they are only able to do their jobs if they fold correctly
and adopt their respective, very specific 3D structure. To ensure that
nothing goes wrong with the folding process, it is strictly monitored
in the cell. The consequences of a flawed quality control can be seen,
for example, in the deposition of misfolded proteins in neurodegenerative diseases such as Alzheimer's. Researchers at the Max Planck Institutes
of Neurobiology and of Biochemistry have now developed a mouse line that
makes the state of protein balance visible in the mammalian brain for
the first time. In this way, the processes of protein quality control
can now be studied in healthy and diseased neurons in more detail.


========================================================================== Proteins fulfill all important tasks in our body: They transport
substances, protect against diseases, support the cell and catalyze
chemical reactions - - to name just a few. With the building instructions
in our genetic code, every protein can be produced as a long chain of
amino acids. However, that's not the end of the story: in order to perform their vital functions, proteins have to fold into complex 3D structures.

Each cell contains a whole machinery that helps proteins to fold,
corrects folding errors and discards misfolded proteins. As a kind of
quality control, the system thus contributes to proteostasis -- the
controlled function of all proteins.

In healthy cells, this quality control works very well. With age, however,
it gradually deteriorates. This can become a problem, especially for
nerve cells.

These cells do not renew themselves and are therefore dependent on stable protein function throughout their lives. In fact, neurodegenerative
diseases such as Alzheimer's, Parkinson's or Huntington's disease have in common that certain misfolded proteins overload the quality control system
and are not disposed of. These proteins accumulate, clump together and eventually form deposits in the brain tissue. Depending on the disease,
this can lead to impaired memory or muscle control -- with no chance
of a cure so far. The ability to enhance the neurons' quality control
could thus present a promising therapeutic option.

New mouse line In order to study the quality control defects in the
individual diseases in more detail, scientists led by Irina Dudanova
developed a new mouse line. With these animals, the state of proteostasis
can be visualized in the mammalian brain for the first time.

The researchers introduced the protein that normally makes fireflies glow
into the neurons of the mouse. Optimized to the body temperature of the
beetle, the protein needs constant help to fold in "warmer" mammals. Only
then can it adopt its correct structure and produce light. In order to precisely track the location of the luminescent protein in the cell,
the scientists additionally labeled it with a dye. In this way, they
showed that the protein is evenly distributed and glows in healthy
neurons. However, if the protein quality control is overstrained, the
beetle protein makes clumps and no longer glows as strongly. The beetle
protein therefore serves as a proteostasis sensor.

The researchers then crossed the newly developed mouse line with mice
that represent different neurodegenerative diseases. In mice showing signs
of Alzheimer's disease, the luminescent protein formed clumps, signaling
strong proteostasis disturbance. Interestingly, this was not the case in
Chorea Huntington mice. Irina Dudanova relates, "The different results
were quite surprising. When we had a closer look at the possible reasons,
we found that both the misfolded proteins themselves and their location
in the cell play an important role." Variation within the cell While
the misfolded protein in the Alzheimer's model forms deposits in the cell
body, it clumps together in the cell nucleus in the Huntington's mice.

Accordingly, protein quality control and its capacity can vary greatly
within a cell. "This shows how complex protein quality control is and
how different its alterations can be in individual neurodegenerative
diseases," explains Irina Dudanova.

With the new mouse line, scientists now have a tool to specifically
investigate this complexity -- both in healthy and in diseased
neurons. Irina Dudanova and her team plan to investigate other neurodegenerative diseases and to find out whether different cell types
in the brain are affected at different rates. In addition, the mouse
line could help to assess the effectiveness of different therapies for neurodegenerative diseases.

========================================================================== Story Source: Materials provided by Max-Planck-Gesellschaft. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sonja Blumenstock, Elena Katharina Schulz‐Trieglaff, Kerstin
Voelkl, Anna‐Lena Bolender, Paul Lapios, Jana
Lindner, Mark S Hipp, F Ulrich Hartl, Ru"diger Klein, Irina
Dudanova. Fluc‐EGFP reporter mice reveal differential
alterations of neuronal proteostasis in aging and disease. The
EMBO Journal, 2021; DOI: 10.15252/embj.2020107260 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210819102709.htm

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