Huntington's, ALS: Where the body fails
Researchers find that cells have the tools to cure Huntington's and ALS -
- they just fail to use them

Date:
February 16, 2022
Source:
Technion-Israel Institute of Technology
Summary:
Huntington's, Alzheimer's, ALS, and multiple other neurodegenerative
diseases share a commonality: they are all characterized by proteins
(different ones for each disease) aggregating in neurons within
the brain and nervous system. Now, scientists have found that the
cells have the mechanisms to clear those aggregates -- they just
fail to activate them.



FULL STORY ========================================================================== Huntington's, Alzheimer's, ALS, and multiple other neurodegenerative
diseases share a commonality: they are all characterized by proteins
(different ones for each disease) aggregating in neurons within the
brain and nervous system. Now, Technion scientists have found that
the cells have the mechanisms to clear those aggregates -- they just
fail to activate them. Their study was recently published in Nature Communications.


========================================================================== Proteins are the building blocks and the functioning units of our
body. Any time the body needs something done, specific proteins are
generated to accomplish it. To do this, the code for the particular
protein is read from the DNA, and the protein is built from sub-units
called amino acids. It is then folded into the 3D shape it needs to
assume. Other proteins, called "chaperones," assist in this folding
process.

Aggregates form when certain proteins form incorrectly. Instead of
performing the function they were supposed to perform, they attach to
each other, creating sizeable clusters that not only are useless, but
also disrupt the cells' normal functionality. Ph.D. student Kinneret
Rozales and M.D./Ph.D. student Amal Younis, working as part of the
research group of Professor Reut Shalgi, examined how the cells respond
to the aggregates building up inside them.

How can we know how a cell feels? We cannot ask it whether it is happy
or in pain. But we can examine which genes the cell expresses. We know
the cell would activate certain genes when it feels stress. On the other
hand, if everything is fine, those genes would not be activated.

Some of what the cell does in response to stress is activating specific chaperones, in an attempt to correct or remove misfolded proteins. But
which chaperones are activated? And which ones are needed to solve the
problem? A great many different chaperones are encoded in the human
DNA. Rozales and Younis examined 66 of them in cells with Huntington or ALS-associated protein aggregates. Some chaperones, they found, only
make things worse. But quite surprisingly, they also found chaperones
that could eliminate the aggregates, curing the cell. The tools to cure
the disease are already within us, encoded by our own DNA! Why then,
if the necessary chaperones exist, do they not cure patients' cells
before neurons degenerate? "It is not enough that the tools exist in the
cell's toolbox," said Prof. Shalgi. "The cell needs to realize there
is a problem, and then it needs to know which out of the many tools
available to it, it should use to solve the problem." Unfortunately,
the group found, this is where the bottleneck lies. In cells with Huntington-associated protein aggregates, the cells sensed there was
a problem, and activated some stress-response chaperones, but not
the correct ones. The cells did not know what was causing the stress,
or what they should do to correct the situation. With ALS-associated aggregates, things were even worse; the cells did not realize that they
need to activate chaperones at all and displayed no signs of stress.

"The cell is a complicated system," said Prof. Shalgi in explaining the surprising findings. "Think of your computer: when something is wrong, sometimes you do not realize it at first. It just responds a bit slower
than it used to, perhaps, or it throws an error message that you ignore
and forget.

When you do realize something wrong -- in the way of a blue screen or a
refusal to start, you, or a technician on your behalf, attempt to diagnose
and solve the problem. Sometimes the solution is found straight away,
but other times it is something that you never encountered before, and you don't know which driver needs to be installed, or piece of hardware needs
to be replaced. It is the same with our cells: they do not always realize
there is a problem, or know how to solve it, even when they do in fact
have the tools to do so. The good news is that since the ability is there,
we hope future treatments can be developed to activate it and employ the
body's own tools to cure these debilitating neurodegenerative diseases."
The study was done in collaboration with the Berlin Lab at the Rappaport Faculty of Medicine and supported by the Israeli Science Foundation
(ISF), the ERC, the Prince Center for Neurodegenerative Disorders,
and the Rappaport Institute.

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by
Technion-Israel_Institute_of_Technology. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Kinneret Rozales, Amal Younis, Naseeb Saida, Anatoly Meller, Hodaya
Goldman, Lior Kellerman, Ronit Heinrich, Shai Berlin, Reut Shalgi.

Differential roles for DNAJ isoforms in HTT-polyQ and FUS
aggregation modulation revealed by chaperone screens. Nature
Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-27982-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220216153908.htm

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