Detailed images of molecule associated with ALS could open door to
therapies

Date:
December 8, 2021
Source:
UK Research and Innovation
Summary:
Scientists have determined the structure of the molecule associated
with amyotrophic lateral sclerosis (ALS) and multiple other
neurodegenerative diseases. The researchers say this discovery
could enable targeted development of new medical interventions
and diagnostic tests.



FULL STORY ========================================================================== Scientists have determined for the first time the structure of the
molecule associated with amyotrophic lateral sclerosis (ALS) and multiple
other neurodegenerative diseases. The scientists at the Medical Research Council (MRC) Laboratory for Molecular Biology in Cambridge, UK, who
led the study, say this discovery could enable targeted development of
new medical interventions and diagnostic tests.


==========================================================================
ALS is the most common form of adult-onset motor neuron disease
and is characterised by the deterioration of neurons responsible for controlling voluntary muscle movements such as walking, talking, chewing,
and breathing.

There is no cure for ALS and no effective treatment to halt or reverse
disease progression.

While the cause of ALS is unclear, it is known that the abnormal clumping
of a protein, known as TDP-43, in nerve cells is the defining pathological hallmark of ALS. The TDP-43 clumps are also a hallmark of frontotemporal dementia (the second most common form of early-onset dementia after
Alzheimer's disease) and common in other neurodegenerative diseases,
including Alzheimer's and Parkinson's.

TDP-43 is found in healthy cells throughout our bodies, but in the brains
of patients with these diseases it clumps together forming 'aggregates'
in the brain.

Although scientists have been aware of this for some time, the potential
to translate this information into treatments has been limited as, until
now, the molecular structure of the TDP-43 aggregates has been unknown.

Now, the team of scientists at the MRC Laboratory for Molecular Biology, working with researchers at the Tokyo Metropolitan Institute of Medical
Science and the Aichi Medical University in Japan, have used cryo-electron microscopy to determine the first molecular structure of TDP-43 aggregates extracted from the donated brains of two individuals who had ALS.



==========================================================================
The study, supported by the Medical Research Council and published in
the journal Nature, discovered previously unseen structural features,
such as a filamentous double-spiral-shaped fold.

The structure of TDP-43 observed in this study from human brain samples
was consistent in samples from different regions of the brains of both individuals, but was different from that seen in previous studies that attempted to recreate TDP-43 aggregates in a test tube.

It was previously thought that TDP-43 interacted similarly to analogous proteins associated with other neurodegenerative diseases such as
Alzheimer's disease. This study suggests however that aggregation of
TDP-43 likely results in different disease mechanisms.

These distinct structural features mean that TDP-43 in the brain is likely
to interact uniquely with diagnostic tools and drugs. The scientists say
that these differences could explain why current diagnostic compounds
based on analogous proteins associated with other neurodegenerative
diseases are poor at diagnosing ALS.

The study presents new possibilities for the development of treatments
using compounds that specifically target structural features of TDP-43, including those responsible for aggregation.



==========================================================================
Dr Benjamin Ryskeldi-Falcon, from the MRC Laboratory for Molecular
Biology, who led the study, said: "There are no diagnostics or
therapeutics for ALS and other diseases associated with TDP-43 and the
first step towards developing these is gaining a better understanding
of TDP-43 itself.

"Now that we know what the structure of aggregated TDP-43 looks like and
what makes it unique, we can use it to find better ways to diagnose the
disease early.

"We're excited to be able to use this blueprint in our lab to start
identifying compounds that bind to unique sites on TDP-43, with the aim
of identifying potential therapies for further study.

"I would especially like to thank the people with ALS, and their
families, who donated their brains to research to help us gain a
better understanding of this terrible disease." Dr Jo Latimer, head
of neurosciences and mental health at the MRC, which funded the study, said:"These findings are an important and much needed contribution to
our understanding of ALS and associated neurodegenerative diseases.

Identifying the structure of a protein that is known to contribute
to disease is the first step towards understanding its role in the
development of disease.

"Currently, the cause of ALS is unclear but understanding the structure
of TDP- 43 will redefine how scientists think about disease progression
and enable them to adopt entirely new approaches to developing therapies
and diagnostics." The research was funded by the Medical Research
Council and also received support from Alzheimer's Research UK, the
Japan Agency for Medical Research and Development and the Japan Science
and Technology Agency.

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


========================================================================== Journal Reference:
1. Diana Arseni, Masato Hasegawa, Alexey G. Murzin, Fuyuki Kametani,
Makoto
Arai, Mari Yoshida, Benjamin Ryskeldi-Falcon. Structure of
pathological TDP-43 filaments from ALS with FTLD. Nature, 2021;
DOI: 10.1038/s41586- 021-04199-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211208123354.htm

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