Stem cell research delivers new points of attack against Parkinson's
disease

Date:
September 11, 2020
Source:
University of Luxembourg
Summary:
An interdisciplinary research team experimented on patient-based
cell cultures in the laboratory. The new combination of active
substances they identified will have to undergo clinical trials
before they can be used to treat patients.



FULL STORY ==========================================================================
In a seven-year research effort, an international team of scientists has clarified the cause for certain genetic forms of Parkinson's disease, and
has identified potential pharmacological treatments. The interdisciplinary research team, led by Prof. Rejko Kru"ger, of the Luxembourg Centre for
Systems Biomedicine (LCSB) of the University of Luxembourg, experimented
on patient- based cell cultures in the laboratory. The new combination
of active substances they identified will have to undergo clinical trials before they can be used to treat patients. The research team published its results today in the scientific journal Science Translational Medicine.


==========================================================================
Lack of protein DJ-1 makes you sick A protein called DJ-1 plays a crucial
role in keeping nerve cells functioning.

If the body is unable to produce ample amounts of DJ-1, important nerve
cells die. The result is the onset of neuro-degenerative diseases such
as Parkinson's. The production of important proteins like DJ-1 can
be disrupted or halted permanently if the genetic blueprints or the
production processes they encode are defective.

Now, Prof. Rejko Kru"ger's research team in Luxembourg has succeeded
in identifying for the first time the importance of an error in the
production process known as 'splicing' in the development of a certain
form of Parkinson's disease. "In the patients, an essential tool
for the assembly of the protein DJ-1 fails to dock properly," Kru"ger
explains. "In scientific terms, we call that exon skipping. As a result of
this defect, the protein doesn't get built at all." The research result
offers an entirely new point of attack for treating this malfunction of
protein synthesis with drugs. "This insight fundamentally changes our view
of the causes of the disease and presents entirely new possibilities for treatment," says Dr Ibrahim Boussaad, LCSB scientist and first author of
the scientific paper. "We could only gain this new understanding thanks
to the skin cells from the patients," Boussaad emphasises.

Cell donation enables progress The Luxembourg Parkinson's Study,
initiated in 2015, includes a group of 800 Parkinson's patients and 800
healthy control subjects. Thanks to the donation of skin cells taken by
small biopsies, the researchers in Luxembourg were able to reprogram
these cells to grow into nerve cells in vitro. These nerve cells are
very similar to the neurons in affected regions of the donor's brain
and can be used for analyses and tests in the laboratory. Because it is
not possible to take neurons directly from the brain of patients, for
health and ethical reasons, reprogramming is the only way to examine the clinical features of the patient's neurons in vitro. In scientific jargon,
this is called a patient-based in vitro model, and is an important step
in personalised medicine. Using this method, Prof. Kru"ger's team was
able to explain the cause of the genetic form of Parkinson's disease in
which the PARK7 gene is mutated.

Prof. Thomas Gasser, a medical director at the Tu"bingen University
Hospital and co-author of the paper, adds, "We are proud to have been
able to contribute our expertise in the reprogramming of patient cells
to this stem cell work of our colleagues in Luxembourg." Institutions
from Germany, Italy and the USA collaborated in the research project.

Luxembourg's interdisciplinarity is a key to this success Precise bioinformatics algorithms developed at the LCSB allowed the research
team to immediately carry out an automated search for potential active substances for drug treatment. This yielded a hit in the form of the
active compounds phenylbutyric acid and RECTAS (RECTifier of Aberrant Splicing).

Administered in combination, these two active substances allow the
cells in the test tube to effectively reactivate the production of the important protein DJ- 1. "Only by combining numerous disciplines --
from medical practice, to laboratory research, to computer science --
could we understand the cause and at the same time identify active
substances for a potential treatment," Prof.

Rejko Kru"ger explains. He adds, "This kind of scientific progress 'Made
in Luxembourg' is possible because all the necessary disciplines have
been unified in Luxembourg for several years now." This work represents
the high point to date of the PEARL program of the Luxembourg National
Research Fund (FNR), through which the research of Prof. Kru"ger and his
team is funded. The team of scientists especially expresses its gratitude
to the people who are participating in the Luxembourg Parkinson's Study
and who have made this research possible in the first place.


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


========================================================================== Journal Reference:
1. Ibrahim Boussaad, Carolin D. Obermaier, Zoe' Hanss, Dheeraj
R. Bobbili,
Silvia Bolognin, Enrico Glaab, Katarzyna Wołyńska, Nicole
Weisschuh, Laura De Conti, Caroline May, Florian Giesert, Dajana
Grossmann, Annika Lambert, Susanne Kirchen, Maria Biryukov, Lena F.

Burbulla, Francois Massart, Jill Bohler, Ge'rald Cruciani, Benjamin
Schmid, Annerose Kurz-Drexler, Patrick May, Stefano Duga, Christine
Klein, Jens C. Schwamborn, Katrin Marcus, Dirk Woitalla, Daniela
M. Vogt Weisenhorn, Wolfgang Wurst, Marco Baralle, Dimitri Krainc,
Thomas Gasser, Bernd Wissinger, Rejko Kru"ger. A patient-based
model of RNA mis-splicing uncovers treatment targets in Parkinson's
disease. Science Translational Medicine, 2020; 12 (560): eaau3960
DOI: 10.1126/scitranslmed.aau3960 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200911093004.htm

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