Genetic Change Triggers Brain Cells to Cause ALS

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Protoplasmic and fibrous astrocytes, illustration
Illustration of a protoplasmic (left) and a fibrous (right) astrocyte. Astrocytes are a type of glial cell. They provide structural support and protection for neurons (nerve cells) and also supply them with nutrients and oxygen. Astrocytes are subdivided into fibrous and protoplasmic types. Protoplasmic astrocytes are found in the brain's grey matter, and have relatively short processes attaching to neuron cell bodies. Fibrous astrocytes, found in the white matter, have much longer processes and attach to axons.

A genetic change that occurs in astrocyte cells in the brain and spinal cord causes them to become ‘reactive’ and trigger the onset of the degenerative motor neuron disease amyotrophic lateral sclerosis (ALS), according to research from University College London and the Francis Crick Institute.

When genes in the disease-causing astrocytes are translated into proteins, the diseased cells seem to undergo a greater degree of editing or ‘splicing’ and are more likely to lose the non-coding intron sections of the sequence. In contrast, the healthy astrocyte proteins contain sequence from both the coding and the intron sections of the genes.

“Understanding how astrocytes undergo this transformation is a really exciting step forward. It brings us closer to potentially being able to control and prevent astrocytes from becoming harmfully reactive,” says Rickie Patani, M.D., PhD., a professor at the Crick Institute who led the research.

“While there’s still a long way to go, we’re hopeful that developing such a treatment is possible and that it could even potentially be used across all neurological conditions in which an increase in reactive astrocytes is also documented, including Parkinson’s and Alzheimer’s.”

ALS is the most common type of motor neuron disease with around 2 people per 100,000 diagnosed around the world per year. There is no cure and people who are affected gradually lose control of their voluntary muscles with most dying 2-4 years after diagnosis due to breathing difficulties.

Astrocytes, star shaped cells in the central nervous system that do not transmit electrical signals, are known to be altered in people with conditions such as ALS, as well as in other conditions like Parkinson’s and Alzheimer’s disease, or in those who have nervous system injuries. They become ‘reactive’ and some start to cause damage to the surrounding motor neurons.

While scientists have known that astrocyte behavior changes in ALS for a while, the reason behind this was unclear.

As described in the journal Nucleic Acids Research, Patani and colleagues compared astrocytes from ALS patients with healthy astrocytes to assess how they differ and what could be behind the change to a reactive state.

The ALS astrocytes seemed to have a lot of heavily spliced proteins where many non-coding introns had not been translated from the gene sequence, whereas in healthy astrocyte cells many intron regions are retained in the final proteins.

The abnormal proteins produced as a result of these cellular change appear to drive the astrocytes to become reactive and cause disease. Notably, the opposite process seems to happen in motor neurons of people with ALS.

“Our group have previously shown that splicing is decreased in ALS motor neurons, so when we found the opposite in ALS astrocytes we were intrigued,” says Oliver Ziff, M.D., lead author on the paper and clinical fellow at the Crick in Patani’s group.

“In fact, increased splicing is what we find in other immune cells when they become activated or angry. This raises the possibility that ALS astrocytes inflict a toxic immune insult on the nervous system and opens new therapeutic avenues for treating ALS.”

The researchers are hoping their findings will help accelerate the development of better treatments for ALS and plan to continue their work in this important area.

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