Europe PMC Team

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[![](https://1.bp.blogspot.com/-XVhsAfvKp38/Uz1h2nvsB7I/AAAAAAAAAGU/QZJ0ZS5oLwY/s1600/6_C_TBPH+gene.jpg){decoding="async"
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width="400"}](http://1.bp.blogspot.com/-XVhsAfvKp38/Uz1h2nvsB7I/AAAAAAAAAGU/QZJ0ZS5oLwY/s1600/6_C_TBPH+gene.jpg){style="margin-left: 1em; margin-right: 1em;"}
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[[Image design:
[Serial/Trash](http://www.serialtrash.com/){target="_blank"
rel="noopener"}]{style="font-size: xx-small;"}]{style="font-family: \"arial\" , sans-serif; line-height: 150%;"}
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[A  
number of genes have been implicated in neurodegenerative diseases such
as  
amyotrophic lateral sclerosis (ALS), also known as motor neurone
disease, and  
Frontotemporal lobar degeneration (FTLD). However, the core biological  
processes involved in these disorders are extremely difficult to model
and this  
is hampering the effort to develop treatments. If we can resolve this
and  
increase our knowledge about these disease processes it may be possible
to  
develop new and improved
treatments.]{style="font-family: \"arial\" , sans-serif; line-height: 150%;"}
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**[The gene TDP-43 in ALS  
and FTLD]{style="font-family: \"arial\" , \"sans-serif\";"}**
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[The  
gene TDP-43 has been shown to be involved in the development of the  
neurodegenerative diseases ALS and FTLD in humans, however the exact
way(s) in  
which it does this still remain unclear. This protein acts as a master  
regulator of RNA, a precursor to proteins, and can therefore control
the  
expression of genes within cells. A recent study by a group led by Dr.
Frank  
Hirth from King's College London has shed some light on this by using
an  
interesting choice of organism: drosophila melanogaster, the common
fruit fly.]{style="font-family: \"arial\" , \"sans-serif\";"}
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**[A fly way to model  
diseases]{style="font-family: \"arial\" , \"sans-serif\";"}**
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[Researchers  
in a wide variety of fields are looking to drosophila to model complex  
diseases. *But why choose flies, they  
couldn't be any more different biologically to us could they?* In
fact,  
fruit flies share many biological processes with us; they have a complex
immune  
system, an intricate brain and can even develop cancer! Genes that are
similar  
in structure and cellular function in flies and human are called
homologues.  
They can be retained from a common ancestor by a process called
evolutionary  
conservation. What makes the fruit fly a great model for studying
disease is  
that it has fewer genes than humans. Where humans often have multiple
genes  
that perform essentially the same function, a feature known as
redundancy,  
flies often only have one gene at each stage of a signalling pathway.
This  
means that if you alter that one gene the effect should be more
obvious.  
Imagine calling in sick for work but no one there is able to cover for
you,  
your work just won't get done and others will see exactly what your role
is!]{style="font-family: \"arial\" , \"sans-serif\";"}
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**[Altering the function of  
fruit fly TBPH models neurodegenerative
disease]{style="font-family: \"arial\" , \"sans-serif\";"}**
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[The  
fruit fly homologue of the TDP-43 gene is called TBPH, and it too has
been  
implicated in neurodegenerative disease. To investigate TBPH the
researchers  
from King's made fruit flies which either lacked the gene, or had
increased gene  
expression. Interestingly, both types of fly have key symptoms of
neurological  
disorders such as a decreased life span and motor dysfunction -- this
was measured  
by videoing the flies walking and then making recordings about the speed
and  
gait of their  movements. TBPH may  
therefore be considered a "goldilocks gene", too much or too little can
be  
biologically bad and "just the right amount" is required for normal
health.]{style="font-family: \"arial\" , \"sans-serif\";"}
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**[What mechanism did this  
study find?]{style="font-family: \"arial\" , \"sans-serif\";"}**
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[To  
discover how loss or gain of TBPH leads to altered motility of the flies
the  
researchers began to compare physical features of the normal fly to
flies with  
loss of TBPH. Firstly they noted that there were no visible differences
between  
muscle or synapse structure. This led them to dig deeper into the
process of  
motor function. Using a series of complex experiments measuring the
electrical currents  
generated at the gaps between neurons and muscles
(neruo-muscular-junctions) of  
TBPH expressing, non-expressing or over-expressing flies, the group were
able  
to suggest that the defects exist at the pre-synaptic stage of signal  
transmission. The flies have trouble transmitting neurological signals
from the  
neurones to the muscles and this causes the physical difficulty in
movement; as  
seen in humans with disorders driven by dysfunctional motor
neurones.]{style="font-family: \"arial\" , \"sans-serif\";"}
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**[Modelling the aging
fly]{style="font-family: \"arial\" , \"sans-serif\";"}**
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[Humans  
typically develop neurological diseases during old age, a fruit fly
model where  
TBPH loss, or over-expression, was targeted only to a specific area of
neurones  
allowed flies to age normally. It was not until flies had reached an
"old age"  
of 40 days that they started to lose pre-synaptic function. This led
ultimately  
to symptoms of neurodegeneration suggesting TBPH loss or over-expression
has a  
progressive effect on neurological degeneration. Therefore, optimal TBPH
levels  
in neurones are critical for maintaining proper motor neuron function
during  
aging and supports both the TDP-43 gene as a driver of motor neuron
disorders.  
This study elegantly highlights the usefulness of the TBPH fruit fly
model as a  
great way to research the underlying mechanisms behind these disorders.
If more  
is discovered about these mechanisms then new and exciting therapeutic
agents  
could be developed for treating neurodegenerative diseases. It is clear
that  
when it comes to neurodegenerative disease research the flies have it!
]{style="font-family: \"arial\" , \"sans-serif\";"}
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*[This summary by John Foster was shortlisted for Access to
Understanding 2014 and was commended by the competition judges.
It describes research published in the following
articl]{style="font-family: \"arial\";"}[e, ]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}*[*selected
for inclusion in the competition by the Motor Neurone Disease
Association*]{style="background-color: white; color: #5a595e; font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif; line-height: 20px;"}*:*
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[[Loss and gain
of ]{style="font-family: \"arial\" , sans-serif; line-height: 19px;"}*Drosophila*[ TDP-43
impair synaptic efficacy and motor control leading to age-related
neurodegeneration by loss-of-function
phenotypes]{style="font-family: \"arial\" , sans-serif; line-height: 19px;"}](http://europepmc.org/articles/PMC3605831){target="_blank"
rel="noopener"}
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[PMCID: PMC3605831]{style="font-family: \"arial\" , sans-serif;"}
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[[D.C. Diaper, Y. Adachi, B. Sutcliffe, D.M. Humphrey, C.J.H. Elliot, A.
Stepto, Z.N. Ludlow, L. Vanden Broeck, P. Callaerts, B. Dermaut, A.
Al-Chalabi, C.E. Shaw, I.M. Robinson & F.
Hirth.]{style="font-size: xx-small;"}]{style="font-family: \"arial\" , sans-serif;"}
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[[*Human Molecular Genetics* (2013) 22(8),
1539-1557.]{style="font-size: xx-small;"}]{style="font-family: \"arial\" , sans-serif;"}
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[  
]{style="font-family: \"arial\" , sans-serif;"}
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<div>

[*[Access to
Understanding](http://www.access2understanding.org/competition/){target="_blank"
rel="noopener"}* entrants are asked to write a plain English summary of
a research article. For *Access to Understanding* 2014 there were 10
articles to choose from, selected by the [Europe PMC
funders](http://europepmc.org/Funders/){target="_blank"
rel="noopener"}. **The articles are all available from Europe PMC, are
free to read and download, and were supported by one or more of the
Europe PMC
funders.**]{style="font-family: \"arial\" , sans-serif; line-height: 24px;"}

</div>

<div>

[  
]{style="font-family: \"arial\" , sans-serif; line-height: 24px;"}

</div>

<div>

[Look out here and on
Twitter [@EuropePMC_news](https://twitter.com/EuropePMC_news){target="_blank"
rel="noopener"} for further competition news and other Europe PMC
announcements.  ]{style="font-family: \"arial\" , sans-serif; line-height: 24px;"}[ ]{style="font-family: \"arial\" , sans-serif; line-height: 24px;"}

</div>
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[Image design: Serial/Trash]{style=“font-family: "arial" , sans-serif; line-height: 150%;”}  [A number of genes have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as motor neurone disease, and Frontotemporal lobar degeneration (FTLD). However, the core biological processes involved in these disorders are extremely difficult to model and this is hampering the effort to develop treatments.

The TBPH gene – Do neurodegenerative diseases have a fly in the ointment?

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[by Nina Rzechorzek (University of Edinburgh,
UK)]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}  
[Short-listed for [*Access to
Understanding*](http://www.access2understanding.org/competition/)
2013]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}  
*[]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}*  
[*[How do nerve cells
die?]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}*]{style="font-family: \"arial\";"}[]{style="font-family: \"arial\";"}  
[]{style="font-family: \"arial\";"}

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[[Many human diseases involve degeneration of the  
nervous system -- a system of interconnecting nerve cells, allowing us
to sense and  
respond to our environment. All of these disorders are incurable and
fatal.  
Most of them share a common feature -- aggregation of abnormal protein
within  
nerve cells. One such protein is TDP-43 which accumulates in some
dementias and  
disorders that affect motor neurones -- the nerve cells that tell our
muscles to  
contract. In a small number of families, motor neurone disease is
inherited  
because the gene that produces TDP-43 is faulty. This confirms that
TDP-43 is  
important in the disease process. It does not explain how changes in
this  
protein cause nerve cell
death.]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}]{style="font-family: \"arial\";"}
:::

  
[Disease models, using animals or generic cells in a  
dish, do not mirror the human condition and need artificially increased
protein  
levels to show an effect. To overcome these issues, the researchers in
this  
study used a cutting-edge technique. It is now possible to take a skin
sample  
from a patient, place the skin cells in a dish, and "re-program" them
into stem  
cells. Stem cells can become any cell type in the body. They can be
multiplied  
and 'instructed' to make motor neurones by exposing them to a few
agents. If the  
donor patient has a faulty TDP-43 gene, all the neurones made from
that  
patient's skin will have faulty TDP-43 protein -- at the relevant
quantity. Skin  
samples from one such patient and two healthy humans were collected
and  
reprogrammed.]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}

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[[![](https://1.bp.blogspot.com/-8gpFAMzOLYk/Umj9_lA18kI/AAAAAAAAAJQ/CCNyO00TV7g/s400/shutterstock_85545598.jpg){decoding="async"
loading="lazy" border="0" height="243"
width="400"}](http://1.bp.blogspot.com/-8gpFAMzOLYk/Umj9_lA18kI/AAAAAAAAAJQ/CCNyO00TV7g/s1600/shutterstock_85545598.jpg){style="margin-left: 1em; margin-right: 1em;"}]{style="font-family: \"arial\";"}
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[3D stylised neurone image]{style="font-size: xx-small;"}
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[Shutterstock Image ID: 85545598 Copyright: Andrii
Muzyka]{style="font-size: xx-small;"}
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*[Testing the
kit]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}*  
[First, the researchers checked the reprogramming  
had worked, and that the faulty gene was present in the stem cells made
from  
the patient. They confirmed that motor neurones could be generated from
all  
samples by showing they contained a specific combination of proteins.
Mature  
nerve cells carry electrical messages, which they transform into
chemical  
messages to communicate with other cells. Electrical messages are
created when  
'gates' in the membrane surrounding the cell are opened and closed. The
gates  
control the movement of charged particles into and out of the cell.
Different  
gates permit passage of different particles, thus producing different
messages.  
The messages can be recorded whilst blocking each type of gate in turn.
In this  
way, the investigators demonstrated that all of the nerve cells were
equipped with  
motor neurone gates. The gates were operating
correctly.]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}

[So the faulty gene did not affect the maturation  
and basic function of the neurones in this study. It did however cause
an  
increase in the level of TDP-43 protein within the cells, and some of
this  
protein was abnormal. All proteins have natural 'shelf-life'; old
proteins must  
be degraded and replaced with new ones. The workers showed that the
healthy and  
diseased neurones were producing the same amount of TDP-43. This
suggested a  
problem of waste-disposal; either the cell recycling machinery was
impaired, or  
it could not break down abnormal TDP-43. The faulty neurones were also
nearly four  
times more likely to die than the healthy neurones. When a survival
system  
within the neurones was inhibited, the healthy neurones coped better
than the  
diseased ones. Together these findings indicated that the patient
neurones were  
more fragile, because they contained abnormal and increased amounts of
TDP-43.]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}

*[An answer in the palm of your
hand]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}*  
  
[Like baking bread, just four ingredients are needed  
to turn skin cells into stem cells. This stem cell 'dough' can be
moulded into  
any cell type of choice, for any body system (e.g. the nervous system).
A few  
more ingredients give these cells a regional identity within that body
system  
(e.g. motor neurone). In the right environment, cells will develop a
'native  
language' so they can interact with their neighbours and perform the
roles  
expected of them, within their cellular community. The motor neurones
here had  
all the tools to carry out their function, but they lacked material to
work on (i.e.  
muscle). The techniques above could be used to make muscle cells and
grow them  
with motor neurones -- the dough can always be
remoulded.]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}

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[Although samples came from only one patient, this  
paper proves that some aspects of this patient's disease can be modelled
in a  
dish. This concept could be extended to any other disease resulting from
a  
faulty gene. By comparing patient samples with those from people with a
normal  
version of the gene we can understand better how the disease develops.
There  
are many ways in which one abnormal protein might lead to cell death --
consider  
the endless routes that could get you from one station to another on
the  
underground. But every route offers a further opportunity to intercept,
delay, or  
reverse the disease process. If we discover how to treat the disease in
a dish,  
we can make headway in treating the
patient.]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}
:::

[]{style="font-family: \"arial\";"}  
[*This entry[[
]{style="color: black; mso-ascii-font-family: Calibri; mso-bidi-font-family: \"Times New Roman\"; mso-fareast-font-family: \"Times New Roman\"; mso-fareast-language: EN-GB; mso-hansi-font-family: Calibri;"}]{style="color: black; mso-ascii-font-family: Calibri; mso-bidi-font-family: \"Times New Roman\"; mso-fareast-font-family: \"Times New Roman\"; mso-fareast-language: EN-GB; mso-hansi-font-family: Calibri;"}*]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}

describes research published in the following article, selected by the
Motor Neurone Disease Association:  
[]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}  
[[Mutant induced pluripotent stemcell lines recapitulate aspects of
TDP-43 proteinopathies and revealcell-specific
vulnerability]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}](http://europepmc.org/articles/PMC3326463)  
[PMCID:PMC3326463]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}

::: {style="line-height: normal; margin: 0cm 0cm 0pt;"}
[Bilada Bilican, Andrea Serio, Sami J. Barmada, Agnes Lumi Nishimura,
Gareth J. Sullivan, Monica Carrasco, Hemali P. Phatnani, Clare A.
Puddifoot, David Story, Judy Fletcher, In-Hyun Park, Brad A. Friedman,
George Q. Daley, David J. A. Wyllie, Giles E. Hardingham, Ian Wilmut,
Steven Finkbeiner, Tom Maniatis, Christopher E. Shaw, and Siddharthan
Chandran]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif; font-size: x-small;"}
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[[*Proc. Natl. Acad. Sci. USA* (2012)**109(15),**
5803--5808]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}]{style="font-size: x-small;"}
:::

[]{style="font-family: \"arial\";"}  
[]{style="font-family: \"arial\";"}  
[[[*[Access to
Understanding](http://www.access2understanding.org/competition/)*
entrants are asked to write a plain English summary of a research
article. For *Access to Understanding 2013* there were 9 articles to
choose from, selected by the [Europe PMC
funders](http://europepmc.org/Funders/).]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}  
[]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}  
**[The articles are all available from Europe PMC, are free to read and
download, and were supported by one or more of the Europe PMC
funders.]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}**  
[]{style="font-family: \"arial\";"}  
[]{style="font-family: \"arial\";"}  
[Look out here and on Twitter
]{style="font-family: \"arial\";"}[[@EuropePMC_news]{style="font-family: \"arial\";"}](https://twitter.com/EuropePMC_news)[
for announcements about the
competition.]{style="font-family: \"arial\";"}]{style="font-family: \"helvetica neue\" , \"arial\" , \"helvetica\" , sans-serif;"}]{style="font-family: \"arial\";"}
:::


[by Nina Rzechorzek (University of Edinburgh, UK)]{style=“font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;”} [Short-listed for
<em>
 Access to Understanding
</em>
2013]{style=“font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;”}
<em>
 []{style=“font-family: "helvetica neue" , "arial" , "helvetica" , sans-serif;”}
</em>
[
<em>
 [How do nerve cells die?]{style=“font-family: "helvetica neue" , "arial" , "helvetica" ,
</em>

Messaggi di Rogue Scholar

The TBPH gene – Do neurodegenerative diseases have a fly in the ointment?

A window into brain disease is only skin deep