Scientists have discovered how certain forms of motor neuron
disease begin and progress at cellular and molecular levels,
revealing potential new ways to slow down or even stop this
process. The team are already working closely with pharmaceutical
companies to use this knowledge to develop new treatments for motor
neuron disease and other neurodegenerative conditions.
By studying cells from patients with motor neuron disease, also
known as amyotrophic lateral sclerosis (ALS), the team from the
Francis Crick Institute and UCL revealed a detailed picture of how
motor neurons - nerve cells in the brain and spinal cord that
control our muscles and allow us to move, talk and breathe -
decline and die.
The research, published in Cell Reports, also shows
that healthy neuron-supporting cells called astrocytes may play a
role in the survival of motor neurons in this type of ALS,
highlighting their potential role in combating neurodegenerative
diseases. The work was co-led by Sonia Gandhi and Rickie Patani,
Group Leaders at the Francis Crick Institute and UCL, and
Consultant Neurologists at the National Hospital for Neurology and
Neurosurgery, Queen Square.
"Understanding how and why neurons die is clearly vital in
neurodegenerative diseases, but part of the puzzle is also
understanding the emerging role of astrocytes in this context,"
The team took skin cells from healthy volunteers and patients
with a genetic mutation that causes ALS, and turned them into stem
cells capable of becoming many other cell types. Using specific
chemical signals, they then 'guided' the stem cells into becoming
motor neurons and astrocytes.
"We manipulated the cells using insights from developmental
biology, so that they closely resembled a specific part of the
spinal cord from which motor neurons arise," explains Rickie. "It's
like changing the postcode of a house without actually moving it.
We were able to create pure, high-quality samples of motor neurons
and astrocytes which accurately represent the cells affected in
patients with ALS."
Using a range of cellular and molecular techniques, the team
tracked motor neurons over time to see what went wrong in the
patient-derived cells compared to those from healthy people. They
found that an important protein known as TDP-43 leaks out of the
nucleus where it belongs, causing a chain reaction that damaged
several crucial parts of the cell's 'machinery'. Defining the
sequence of molecular events that led to motor neuron death in an
experiment using human-derived cells is an important step
"It's a case of the right protein in the wrong place," says
Rickie. "When TDP-43 leaves the cell nucleus, it causes a series of
problems inside the cell that together lead to cell death."
"Knowing when things go wrong inside a cell, and in what
sequence, is a useful approach to define the 'critical' molecular
event in disease," says Sonia. By modelling the human disease in a
dish, we found that this well-recognised event in ALS occurred
early, and some time before the neurons showed other signs of
stress. One therapeutic approach to stop sick motor neurons from
dying could be to prevent proteins like TDP-43 from leaving the
nucleus, or try to move them back."
The team suspected that astrocytes from the patients' cells
might also be affected, becoming less efficient over time and
eventually dying. To test this, they mixed different combinations
of healthy and ALS patient-derived motor neurons and astrocytes,
and followed their fate using highly sensitive imaging approaches.
They found that healthy astrocytes kept sick motor neurons alive
and functioning for longer, but sick astrocytes struggled to keep
even healthy motor neurons alive.
"Our work, along with other studies of ageing and
neurodegeneration, would suggest that the cross-talk between
neurons and their supporting cells is crucial in the development
and progression of ALS," says Rickie.
The research was funded by Wellcome, Cerevance, Grand
Challenges, the National Institute for Health Research (NIHR) Queen
Square Dementia Biomedical Research Unit and the NIHR University
College Hospitals Biomedical Research Centre.
The paper 'Progressive motor neuron pathology and the role of
astrocytes in a human stem cell model of VCP-related ALS' is
published in Cell Reports.