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BCL11A: Evidence for neuroprotective effect

14/09/2021 Universität Bonn

Researchers at the University of Bonn investigate the role of the
transcription factor for dopamine-producing neurons

The neurotransmitter dopamine influences the activity of a wide variety of
brain areas. A deficiency of this substance can have drastic consequences:
The death of dopamine-producing nerve cells in the substantia nigra - a
particularly sensitive part of the brain - is what causes the core symptoms
of Parkinson's disease. An international team from the University of Bonn
has now investigated the role played by the transcription factor BCL11A in
mice and human cells. If this important factor is missing, the neurons are
even more sensitive and more likely to die. The researchers suspect that
BCL11A plays a protective role for neurons. The study is now published in
Cell Reports.

The human midbrain contains nerve cells that produce dopamine (dopaminergic
neurons). "This neurotransmitter influences other neurons by amplifying or
dampening their activity," explains Prof. Dr. Sandra Blaess from the
Institute for Reconstructive Neurobiology at the University Hospital Bonn.
Like the treble and bass controls on a radio, these special neurons do not
change the song or the tune, but they can drastically alter the effect.
Dopamine-producing neurons also play a major role in Parkinson's disease:
the dopamine cells located in the substantia nigra, a dark-appearing
structure in the midbrain, die off. The resulting lack of dopamine causes
the movement dysfunctions associated with the disease.

The dopamine-producing neurons form extensive connections in a large number
of brain areas, for example in the cerebral cortex or the striatum. "This
raises the question of whether there are specialized groups within these
dopaminergic neurons that affect only certain areas of the brain," Dr.
Emmanouil Metzakopian of the UK Dementia Research Institute at The
University of Cambridge explains, who contributed data on human cells to the
study. The transcription factor BCL11A is known to be important for
determining cell properties, for example in the cerebral cortex and also in
the immune system. Prof. Blaess' team now investigated for the first time
what role BCL11A plays in the different properties of dopaminergic neurons.

Labeling with fluorescent molecules

The researchers analyzed both developing and mature mouse brains and human
cells to determine in which of the dopamine neurons the transcription factor
BCL11A is switched on. They then labeled BCL11A-producing neurons in mice
with fluorescent molecules, which then lit up under the microscope.

"This allowed us to see which neighboring brain regions the extensions of
these dopaminergic neurons grew into," explains Blaess, who is also a member
of the Collaborative Research Center 1089 "Synaptic Micronetworks in Health
and Disease" and the Transdisciplinary Research Area "Life and Health" at
the University of Bonn. The areas in the brain with which the
BCL11A-positive dopamine-producing neurons made contact were not arbitrary.
For example, the target region was not the entire striatum, which is part of
the complex motor control circuits of the cerebrum, but only a small part of
this brain area.

Substantia nigra particularly susceptible to neurodegeneration

The researchers investigated neurodegenerative processes in the substantia
nigra using mice from the German Center for Neurodegenerative Diseases
(DZNE), which had a loss of dopamine-producing neurons, similar to
Parkinson's disease. "It is known that in Parkinson's patients, dopaminergic
neurons in the substantia nigra die off to a greater extent than neurons in
other brain regions," says Prof. Dr. Donato Di Monte of the DZNE, who was
involved in this part of the study. "This area is therefore considered
particularly sensitive to neurodegeneration."

The team compared dopamine neurons with and without BCL11A in the
"Parkinson's mice". In the substantia nigra, this transcription factor
marked dopaminergic neurons that were particularly susceptible to
neurodegeneration. If the researchers switched off the production of BCL11A
in these cells, even more of the dopamine cells perished. "This suggests
that BCL11A may have a neuroprotective function," says Prof. Blaess,
summarizing the main finding. The molecular mechanism behind this still
needs to be investigated in more detail in further studies. Whether the
findings can be transferred from mice to humans will also be investigated.

Participating institutions and funding

In addition to the Institute of Reconstructive Neurobiology, the Institute
of Anatomy and the Department of Neuropathology of the University of Bonn,
the German Center for Neurodegenerative Diseases (DZNE), the University of
Ulm, the University of Cambridge, the UK Dementia Research Institute (UK
DRI) at Cambridge and the University of Hong Kong are involved. The study
was mainly funded by the German Research Foundation (DFG).
Publication: Marianna Tolve, Ayse Ulusoy, Nikolaos Patikas, K. Ushna S.
Islam, Gabriela O. Bodea, Ece Öztürk, Bianca Broske, Astrid Mentani, Antonia
Wagener, Karen M. J. van Loo, Stefan Britsch, Pengtao Liu, Walid T. Khaled,
Emmanouil Metzakopian, Stephan L. Baader, Donato A. Di Monte, Sandra Blaess:
The transcription factor BCL11A defines distinct subsets of midbrain
dopaminergic neurons, Cell Reports, DOI:
https://doi.org/10.1016/j.celrep.2021.109697
Attached files
  • Dopaminergic neurons in the midbrain of a mouse(red): Neurons producing the transcription factor BCL11A appear in green.Image: Marianna Tolve
  • Prof. Dr. Sandra Blaess from the Institute forReconstructive Neurobiology at the University Hospital Bonn. Photo: BarbaraFrommann/University of Bonn
14/09/2021 Universität Bonn
Regions: Europe, Germany, United Kingdom, Asia, Hong Kong
Keywords: Science, Life Sciences

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