Could you begin by explaining what
amyotrophic lateral sclerosis (ALS) is and how
it affects motor neurons in the spinal cord?
ALS is one of the most complex
neurodegenerative diseases, where the motor
neurons in the spinal cord, brainstem and
the brain deteriorate. Because it is the motor
neurons that are primarily affected, the patient
cannot move, but can remember and still have
cognitive function. The neurons in the brain and
spinal cord that are important for movement
die, which results in paralysis and, eventually,
death. However, other neurons remain relatively
healthy in the patient.
Why did you become interested in studying
ALS? What made it particularly important for
you to focus your research on corticospinal
motor neurons (CSMN)?
The reason has a personal touch behind it. I lost
my brother to a thalamic stroke at the age of 23
and, at the time, knew nothing about the brain. I
changed my topic and programme, and earned
a PhD in the fields of cell biology, anatomy and
neuroscience at Louisiana State University
Health Sciences Center. After that, I went to
the Harvard Medical School Neurosurgery
Department for postdoctoral studies.
I focused on corticospinal motor neurons
during my studies and these are the neurons
that die in ALS patients’ brains. I immediately
developed a personal bond with the patients,
their caregivers and loved ones.
You were the first person to label, isolate and
culture CSMN. What did you discover about
these upper motor neurons’ requirements for
survival and growth?
We found many cellular pathways and events
that are crucial for the function and health
of CSMN. When these cellular events are
perturbed, or become dysfunctional, CSMN
begin to show signs of vulnerability and early
degeneration. One example is the endoplasmic
reticulum (ER) stress; when there is increased
ER stress, other neurons manage to cope with
it, but CSMN cannot do so as effectively as
other neurons.
Your team received a Northwestern University
Translational Innovation Award for creating
an effective method for selectively targeting
CSMN without affecting other neuron
populations. How does this retrograde
transduction approach work?
Transducing just the neurons of interest is
extremely important for developing long-term
and effective treatment strategies. The cerebral
cortex is complex, with billions of neurons
that are different in type, function, size and
shape, and all interconnected with each other.
However, in diseases, not all neurons show
initial vulnerability; for reasons still unknown,
only a select set of neuron populations
show primary vulnerability and undergo
degeneration. When we better understand the
causes that underlie these diseases, we will
want to deliver the therapies directly to these
neurons, without affecting other neurons in the
brain so that we do not perturb their balance.
How did you come to generate and
characterise a reporter line that made upper
motor neurons visible in the brain?
We searched thousands of genes that
showed high levels of expression in CSMN
and are longlasting and stable. UCHL1 gene
is expressed in almost all neurons to varying
degrees, but CSMN express high levels, with
expression present even at very old ages.
We therefore chose to generate using a BAC
construct that expresses the eGFP gene under
the control of UCHL1 promoter.
Finally, how important is it for women to be
fostered in science and technology to help
drive innovation forward?
I think women have the potential to lead the way
in innovation because they have a different way
of leading – with understanding, compassion
and desire. Innovation stems from our ability
to see what others do not, and is fuelled by our
will to make a difference in the world. In my
opinion, women have an intrinsic ability to be
innovative and creative. When given an equal
chance, women always do well and exceed
any expectations. Thus, in addition to being
a scientist, I am a keen supporter of women
in science.
I am one of the Women in STEM faculty
members and am on the board of the Turkish
American Women Scholar Fund (TAWSF),
which funds the college education of young
women who are accepted to universities but
have socioeconomic limitations. So far, we have
helped over 125 female students to graduate
and we will continue to offer assistance.
Dr Hande Özdinler
is a neurobiologist whose research into upper motor neuron biology has
unearthed many significant findings. She discusses her motivations and vision for her own research
and that of young women scientists
Highlighting the importance
of upper motor neurons
INTERNATIONAL INNOVATION
NEUROSCIENCE
1
Researchers at the
Northwestern University Feinberg School of Medicine
, USA,
have made several important findings in their research on a neurodegenerative
disorder that renders patients paralysed. In facilitating analysis of specific
neurons, there is hope of a cure in the future
Hopes for the future of
neurodegenerative diseases
AMYOTROPHIC LATERAL SCLEROSIS
(ALS)
is a disorder that leads to the deterioration
of neurons in the spinal cord, brainstem and
brain. As many of these neurons control
voluntary movement, patients are often
rendered paralysed by the condition. The
disorder is known also as Lou Gehrig’s disease,
named after the former American baseball
player whose career – and life – was tragically
cut short as a result of this disease. Currently,
there is no known cure for the condition, which
affects two in every 100,000 people.
Attempts to understand the underlying causes
of neurodegenerative diseases such as ALS
are challenging for various reasons. Not only is
the brain one of the most complex organisms
known to science, it is made up of billions upon
billions of neurons and non-neuronal cells.
These vast numbers make it extremely difficult
to pinpoint the specific neuron populations
affected by ALS, thereby hindering
development of effective
treatment strategies.
Indeed, in addition to the
thousands of different types of
neurons and non-neuronal cells,
ALS is known to only affect some
neurons and, even then, does not
affect them to the same degree.
While some neurons might show
vulnerability from the outset of
the disease, others appear to be
intact. The complexity of the brain
makes isolating those affected
neurons from their unaffected
counterparts particularly difficult, but is a
necessary step in understanding why they
become vulnerable and degenerate in patients.
SPOTLIGHTING SPECIFIC NEURONS
Over the past few years, researchers at the
Northwestern University Feinberg School
of Medicine have given cause for hope in
successfully treating this extremely debilitating
condition. Led by Dr Hande Özdinler, the
team has developed innovative approaches to
studying the biology of motor neurons in the
brain that become vulnerable as a result of
ALS. Indeed, Özdinler became the first person
to label, isolate and culture the corticospinal
motor neurons (CSMN), in an effort to
understand their requirements for survival.
CSMN are extremely complex neurons and
control voluntary motor function. They are
therefore of particular interest to researchers
investigating ALS. Özdinler’s research now
enables direct investigation of CSMN by
employing novel cellular and molecular
approaches. “Being able to see the neurons
that become vulnerable in the disease has
been very important, because for the first time
we were able to see and identify them within
the complex and heterogeneous structure of
the brain,” explains Özdinler. “This allowed
their isolation as a pure neuron population and
determined why they become vulnerable in the
disease while others remain healthy.”
ENABLING APPLICATION DEVELOPMENT
Finding a means of accessing the information
directly from the neurons affected by ALS is
LES TURNER ALS SYMPOSIUMS
Özdinler is organising meetings and
symposiums to bring people together
so that new research projects can be
initiated. To find out more, visit:
http://bit.ly/fourth_ALS_symposium
http://bit.ly/fifth_ALS_symposium
www.internationalinnovation.com
2
BRINGING LIGHT TO THE UPPER MOTOR NEURONS
IN AMYOTROPHIC LATERAL SCLEROSIS
OBJECTIVES
• To further understanding of the causes of
amyotrophic lateral sclerosis (ALS) through using
innovative approaches to study corticospinal motor
neurons (CSMN)
• To emphasise the crucial role that upper motor
neurons play in the development of ALS to help find
a cure
PARTNERS
Cognitive Neurology and Alzheimer’s Disease
Center, USA
Robert H Lurie Comprehensive Cancer Research
Center at Northwestern University, USA
FUNDING
Les Turner ALS Foundation
ALS Association
US National Institutes of Health (NIH)
CONTACT
Dr Hande Özdinler
Assistant Professor in Neurology
Feinberg School of Medicine
Northwestern University
303 E Chicago Ave
Chicago
Illinois 60611
USA
T +1 312 503 2774
E ozdinler@northwestern.edu
http://bit.ly/Ozdinler_profile
http://bit.ly/Ozdinler_lab
@DrOzdinler
http://bit.ly/LI_Ozdinler
HANDE ÖZDINLER
is trained in
the fields of molecular biology,
genetics, cell biology, anatomy and
neuroscience. Her research focuses
on CSMN and she is Founding
Director of the second Les Turner ALS Laboratory at
Northwestern University, USA. She received awards
from Harvard and Northwestern University for her
ability to study these neuron populations in detail.
of extreme importance and enables analysis
of those of specific interest without affecting
other neurons. Previous research endeavours
have used cell lines that are not related to the
disease, or differentiated neurons that are
forced to become one neuron type, despite
carrying many different variations. Özdinler’s
research is exciting because it moves away
from former practices, uncovering many of the
mysteries associated with ALS. “We are at the
doorstep of many important discoveries,” she
says. “Our research will reveal the mystery
of why these neurons die, while others
remain healthy.”
Finding a means to analyse the neurons
involved in the paralysis associated with ALS
– without unduly affecting other neurons – is
crucial to the development of successful
therapeutic applications. Finding an effective
treatment for the condition is one thing, but
unless that treatment can be delivered to the
cells responsible, any treatment will remain
ineffective. As their studies continue, so too
does the impact of their findings, with other
studies revealing potential detection markers
for the diseases in which CSMN are affected,
including hereditary spastic paraplegia, primary
lateral sclerosis as well as ALS.
PULLING IN THE SAME DIRECTION
Özdinler’s research is funded and supported
by the US National Institutes of Health (NIH),
the ALS Association and, most significantly, by
the Les Turner ALS Foundation, which Özdinler
readily acknowledges: “Foundations are the
engines of innovation. They are founded by
people who want to implement change and have
the energy and desire to make that happen.
They generate a momentum that no one can
resist. If there were no active foundations for
causes that are important, we would not be able
to move the field forward at such a speed”.
The ALS Association is the largest in the US,
and the Les Turner ALS Foundation is one of
the first foundations in the world to promote
a better life for patients affected by ALS, and
encourages and facilitates research into
understanding the biology of the disease and
finding an effective cure.
ALS associations and foundations have
embraced initiatives like the ‘ice bucket
challenge’ to provide people with a voice to
communicate their desire to stop the disease. It
is important that researchers such as Özdinler
take up the challenge laid before them to make
a real difference to people’s lives. “Now the ball
is in our court,” says Özdinler. “We have to be
as ambitious as the patients and caregivers to
find a cure. It’s not really about papers, grants
and promotions – it is about getting together to
work towards a solution.”
Özdinler’s research has highlighted the
important role that upper motor neurons play
in motor neuron diseases where movement
is impaired, thereby encouraging other
researchers around the world to focus their
energies on these particular neurons to develop
a cure. Emphasising this importance could
signal positive change for ALS patients, which
is certainly something to be celebrated.
FUNDING SUCCESS
To continue research on amyotrophic lateral sclerosis (ALS), Özdinler was awarded
over US $2.5 million in new grants from the US National Institutes of Health (NIH) and
the ALS Association – a record amount for a single young investigator to receive at one
time. Visit:
http://bit.ly/Ozdinlar_grants
AAV-GFP serotypes
and
red fluorescent
microspheres
AAV-GFP serotypes
and
red fluorescent
microspheres
AAV-GFP serotypes
AAV-GFP serotypes
DIRECT CORTICAL INJECTION
CORTICOSPINAL TRACT INJECTION
Red fluorescent
microspheres
Red fluorescent
microspheres
INTERNATIONAL INNOVATION
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