Patients’ stem cells point to potential treatments for motor | Cosmos – Cosmos
By Sykes24Tracey
Physicist Stephen Hawking is perhaps the most famous sufferer of motor neuron disease, a crippling degenerative condition that affects an estimated 150,00 people around the world.
Karwai Tang / Getty
In news that may bring hope to Stephen Hawking and hundreds of thousands of others around the world, British scientists have used reprogrammed skin cells to study the development of motor neuron disease.
Its like changing the postcode of a house without actually moving it, explains neuroscientist Rickie Patani, referring to research offering startling new insights into the progress and treatment of the crippling degenerative condition, also known as amyotrophic lateral sclerosis (ALS).
Patani, together with colleague Sonia Gandhi, both from the Francis Crick Institute and University College London, in the UK, led a team of researchers investigating how the disease destroys the nerve cells that govern muscle movement.
The results, published in the journal Cell Reports, comprise the most fine-grained work to date on how ALS operates on a molecular level and suggest powerful new treatment methods based on stem cells.
Indeed, so exciting are the implications of the research that Ghandi and Patani are already working with pharmaceutical companies to develop their discoveries.
The neurologists uncovered two key interlinked interactions in the development of motor neuron disease, the first concerning a particular protein, and the second concerning an auxiliary nerve cell type called astrocytes.
To make their findings, the team developed stem cells from the skin of healthy volunteers and a cohort carrying a genetic mutation that leads to ALS. The stem cells were then guided 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, says Patani.
We were able to create pure, high-quality samples of motor neurons and astrocytes which accurately represent the cells affected in patients with ALS."
The scientists then closely monitored the two sets of cells healthy and mutated to see how their functioning differed over time.
The first thing they noted was that a particular protein TDP-43 behaved differently. In the patient-derived samples TDP-43 leaked out of the cell nucleus, catalysing a damaging chain of events inside the cell and causing it to die.
The observation provided a powerful insight into the molecular mechanics of motor neuron disease.
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 Ghandi.
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 second critical insight was derived from the behaviour of astrocytes, which turned out to function as a kind of nursemaid, supporting motor neuron cells when they began to lose function because of protein leakage.
During the progression of motor neuron disease, however, the astrocytes like nurses during an Ebola outbreak eventually fell ill themselves and died, hastening the death of the neurons.
To test this, the team did a type of mix and match exercise, concocting various combinations of neurons and astrocytes from healthy and diseased tissue.
They discovered that healthy astrocytes could prolong the functional life of ALS-affected motor neurons, but damaged astrocytes struggled to keep even healthy motor neurons functioning.
The research reveals both TDP-43 and astrocytes as key therapeutic targets, raising the possibility that the progress of ALS might be significantly slowed, or perhaps even halted.
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 Patani.
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Patients' stem cells point to potential treatments for motor | Cosmos - Cosmos
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