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Europe PMC team

 | 4 November 2013


A window into brain disease is only skin deep

by Nina Rzechorzek (University of Edinburgh, UK)
Short-listed for Access to Understanding 2013

How do nerve cells die?

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.

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

3D stylised neurone image
Shutterstock Image ID: 85545598 Copyright: Andrii Muzyka

Testing the kit
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.

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.

An answer in the palm of your hand

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.

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.

This entry describes research published in the following article, selected by the Motor Neurone Disease Association:

Mutant induced pluripotent stemcell lines recapitulate aspects of TDP-43 proteinopathies and revealcell-specific vulnerability

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
Proc. Natl. Acad. Sci. USA (2012)109(15), 5803–5808

Access to Understanding 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.

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.

Look out here and on Twitter @EuropePMC_news for announcements about the competition.

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