Scientists discover a new molecular pathway shared by two
neurodegenerative disorders

Date:
February 28, 2022
Source:
NIH/National Institute of Neurological Disorders and Stroke
Summary:
Researchers from two independent research teams have discovered
how the mislocalization of a protein, known as TDP-43, alters the
genetic instructions for UNC13A, providing a possible therapeutic
target that could also have implications in treating amyotrophic
lateral sclerosis (ALS), frontotemporal dementia (FTD), and other
forms of dementia. ALS and FTD are two neurodegenerative disorders
in which many cases are linked by mislocalization of TDP-43,
where instead of being primarily located in the nucleus of the
cell where genes are activated, it forms aggregates outside the
nucleus in multiple neurodegenerative diseases.

Rare mutations in the TDP-43 gene are known to cause ALS, but
almost all cases of ALS show mislocalization of TDP-43.



FULL STORY ========================================================================== Researchers from two independent research teams have discovered how
the mislocalization of a protein, known as TDP-43, alters the genetic instructions for UNC13A, providing a possible therapeutic target that
could also have implications in treating amyotrophic lateral sclerosis
(ALS), frontotemporal dementia (FTD), and other forms of dementia. ALS and
FTD are two neurodegenerative disorders in which many cases are linked
by mislocalization of TDP-43, where instead of being primarily located
in the nucleus of the cell where genes are activated, it forms aggregates outside the nucleus in multiple neurodegenerative diseases. Rare mutations
in the TDP-43 gene are known to cause ALS, but almost all cases of ALS
show mislocalization of TDP-43. The studies were published in Nature.


==========================================================================
"ALS and FTD patients have long participated in genetic studies looking
for changes in genes that might contribute to risk for disease," said
Thomas Cheever, Ph.D., program director at the National Institute of Neurological Disorders and Stroke (NINDS). "Here, we see two independent research teams converging to explain how one of these changes can be
a critical factor contributing to an entire class of neurodegenerative diseases, as well as a potential therapeutic target." One study, which is
a collaboration between the labs of Michael Ward, M.D., Ph.D., scientist
at the National Institutes of Health's NINDS, and Pietro Fratta, Ph.D., professor at the University College London Queen Square Motor Neuron
Disease Centre in the United Kingdom, initially looked at lab-grown
neurons derived from human induced pluripotent stem cells (iPSCs) -- stem
cells created from a patient's tissue sample, often skin or blood. Using powerful genetic tools, the researchers created neurons that made much
less TDP-43 protein than normal, and this resulted in the appearance
of abnormal mRNA sequences inserted into the instructions used to make
several other proteins.

These abnormally inserted sequences, called cryptic exons, can result in a defective protein or can even prevent the protein from being made at all.

The UNC13A gene is important for maintaining the connections between
neurons and has been shown to be a risk factor for both ALS and
FTD. UNC13A is also one of the mRNA sequences that contained cryptic
exons when TDP-43 was reduced, and cryptic exons were also seen in
neurons taken from postmortem tissue of ALS and FTD patients. These
findings directly link a well-established risk factor for ALS and FTD
with the loss of TDP-43.

"We have built on years of genetic research that identified that UNC13A
was implicated in motor neuron disease and FTD and supported it with a
new molecular biology finding that confirms that the gene is absolutely fundamental to the disease process," said Dr. Ward.

At the same time, Aaron Gitler, Ph.D., professor at Stanford University
in Stanford, California, and his lab, along with a team led by Len
Petrucelli, Ph.D., professor at Mayo Clinic in Jacksonville, Florida, were
also looking at the effects caused by a loss of TDP-43 as they pertained
to FTD and ALS. They first analyzed existing datasets in which postmortem neurons from patients with FTD or ALS were sorted based on whether their nucleus contained TDP-43. When genes were compared between neurons with
and without TDP-43, UNC13A again emerged as one that was significantly
affected by TDP-43 loss. Knocking down TDP-43 in otherwise healthy cells
also introduced cryptic exons into the UNC13A gene, suggesting that this
is a direct effect on the gene itself. They also show that the genetic
code differences in the variants of UNC13A that are associated with
FTD and ALS occur where the cryptic exon is located. It is known that mislocalization of TDP-43 similarly causes cryptic exon splicing into
another gene that encodes the protein stathmin 2, which is depleted in
the motor neuron and implicated in neurodegeneration. Both studies suggest
that developing means to increase the levels of UNC13A or stathmin 2 may
be effective in preventing the death of neurons in these tragic disorders.

TDP-43 mislocalization is seen in other degenerative diseases, including Alzheimer's disease, chronic traumatic encephalopathy (CTE), limbic predominant, age-related TDP-43 encephalopathy (LATE), and inclusion
body myopathy, suggesting that these findings could be extended to those conditions as well.

The studies were supported in part by the Intramural Research Program at
NINDS, and grants from NINDS (NS097263, NS097273, NS123743, NS084974,
NS104437, NS120992, and NS113636) and the National Institute on Aging (AG071326, AG06267, and AG006786).

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Content may be edited for style and length.


========================================================================== Journal References:
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Link to news story: https://www.sciencedaily.com/releases/2022/02/220228161621.htm

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