A new study identified a group of sporadic amyotrophic lateral sclerosis (ALS) patients whose disease may arise from a group of “jumping genes” unleashed when TDP-43 protein accumulates in clumps in the brain and spinal cord. These “jumping genes” — which can randomly hop from one location on a person’s genes to another — could be at the root of nerve cell loss seen in these individuals.
These findings may have implications for other neurological diseases, and open new paths to find better diagnostic tools and more effective treatment for ALS, the researchers believe.
Their study, “Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia,” was published in the journal Cell Reports.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurological disorder that causes the motor neurons that control voluntary movements to shrink and die off. The loss of motor neurons over time in the brain and spinal cord makes patients progressively lose the ability to control their movements.
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In an effort to understand how gene alterations can contribute to ALS, a team led by Molly Gale Hammell, a professor and group leader at Cold Spring Harbor Laboratory (CSHL) in New York, looked at the role of a protein called TDP-43, which commonly accumulates in the brain and spinal cord of people with ALS.
Hammell and her team analyzed the genes turned on and off — or gene expression patterns — in 148 post-mortem brain samples of ALS patients. The researchers found evidence of the existence of three different groups of patients.
Two groups are marked by stress and inflammation in the brain, along pathways already known to associate with ALS. However, a third group, comprised of 20% of the patients, showed activation of a type of “jumping genes” — called retrotransposons — tied with a malfunction of the TDP-43 protein.
Retrotransposons are one type of transposons. These are genetic elements that have a particular, viral-like behavior. They can lay dormant within the body’s genome — the complete set of genetic material inside a person’s cells — for many years, but when active they can randomly hop from one location on the genome to another. This can cause mutations as the retrotransposons break the surrounding DNA sequence. They also can alter gene expression, meaning how many and to what extent genes are turned on or off.
Mounting evidence has implicated the activity of transposons in human diseases, in particular, neurodegenerative diseases like ALS.
Clumps of TDP-43 protein often form in the motor cortex — the region of the cerebral cortex involved in the control and execution of voluntary movements — and spinal cord of people with sporadic ALS. These are the two tissues where motor neuron loss occurs.
Under normal conditions, TDP-43 is one of the proteins that keep retrotransposons silent, preventing them from jumping and potentially corrupting other parts of the genome. But when TDP-43 forms clumps inside nerve cells — as occurs in people with sporadic ALS — it loses its ability to shut down these elements.
“These jumping genes are telling us about patients who have TDP-43 pathology,” Hammell said in press release. “We really don’t know why one patient would have one set of symptoms versus another, and we’re trying to answer that question.”
Hammell’s team studied the gene expression profile of post-mortem brain tissues of ALS patients with and without TDP-43 accumulation. They saw that retrotransposons were reactivated in patients who had stronger TDP-43 malfunction, or pathology. In a more detailed analysis, the team confirmed that “TDP-43 directly binds retrotransposons in cells and contributes to their silencing,” according to the researchers.
Now, these researchers want to find out if and how these “jumping genes” contribute to the degeneration of nerve cells in ALS. The team believes these genes can be found in viruses or other types of infections. If so, it may be possible to directly target them using antiviral agents or other therapies.
“That’s one of the things we’re really excited about as a possibility,” Hammell said. “Going forward, we want to understand whether transposons are causing the disease, and whether they’re involved in other diseases that also tend to have TDP-43 aggregates, like frontotemporal dementia and some subset of Alzheimer’s.”
In addition, researchers suggest that the existence of distinct groups of ALS patients “might explain why many treatments identified in laboratory models targeting a specific pathway have failed to translate to successful clinical trials.”
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