Scientists at the Francis Crick Institute and UCL have identified a trigger for a major cellular change in amyotrophic lateral sclerosis (ALS), a type of motor neuron disease. The results could help develop new treatments for many neurodegenerative diseases with the same change, including Parkinson’s and Alzheimer’s.
When the nervous system is injured, injured, or infected, astrocytes, called astrocytes, undergo “reactive” changes in their behavior. While some of these reactive astrocytes become protective, others become harmful and damage the surrounding motor neurons.
Reactive astrocytes have been observed in several neurodegenerative diseases including ALS, but there is a lack of understanding of the reasons why astrocytes undergo this change.
In their research published in Nucleic Acid Research Today (March 4) scholars
Comparison of diseased astrocytes with ALS with healthy astrocytes to reveal how diseased cells interact. These cells have grown from human induced pluripotent stem cells – master stem cells – which can be directed to differentiation into any cell in the human body.
They found that the key to stellar change in diseased cells is the increased removal of introns (non-coding sections of genetic information) from RNA in a process called splicing. The team determined that in healthy astrocytes there are some RNAs that usually retain some introns, but in diseased cells these special introns are divided.
This has dire consequences for cell actions. When these introns are cut from RNA, the remaining exons (sections that encode genetic information) are used as a recipe for building proteins and some of these proteins play a role in altering astrocytes.
“Understanding how astrocytes undergo this transformation is a really exciting step forward,” says Ricky Pattani, lead author and group leader at Crick, a professor at the Queen Square Institute of Neurology at the University of California, and a consultant neurologist at the National Hospital of Neurology and Neurosurgery. It brings us closer to being able to control astrocytes and prevent them from becoming a deleterious reactivity.Although there is still a long way to go, we hope that the development of such a treatment will be possible and that it is likely to be used in all neurological conditions in which an increase is also documented. Reactive astrocytes, including Parkinson’s disease and Alzheimer’s disease.
ALS is a rapidly developing degenerative disease. Patients typically experience loss of movement, speech and eventual ability to breathe, and most people only live 3 to 5 years after diagnosis. There are currently no treatments that can benefitfully alter the prognosis.
But understanding the key cellular changes associated with ALS could help develop new treatments to slow the disease’s progression.
Oliver Zeff, lead author and clinical fellow at Crick, Queen Square Institute of Neurology and Registrar of Neurology at the National Hospital of Neurology and Neurosurgery, says: “Our group has previously shown that splicing decreases in ALS motor neurons, so when we found the opposite In astrocytes ALS that have piqued our interest. Indeed, increased splicing is what we find in other immune cells when they become active or angry. This raises the possibility that ALS astrocytes may cause a toxic immune insult to the nervous system and opens up new therapeutic avenues for treating ALS.
Researchers will continue this work to understand the molecular mechanisms involved when astrocytes become reactive with the ambition to develop an intervention that clinicians could use to slow disease progression.
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Notes to Editors
Reference: Ziff, O. et al. (2021). Reactive astrocytes in ALS show a decrease in intron retention. Nucleic Acid Research. DOI: 10.1093 / nar / gkab115
The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the underlying biology of health and disease. Her work helps to understand why disease develops and translate discoveries into new methods of preventing, diagnosing and treating diseases such as cancer, heart disease, stroke, inflammations and neurodegenerative diseases.
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