Agglutination of TDP-43 in ALS Related to Age-Related Loss in the Cellular Control System


The loss of chemical changes in the regulatory sequence of TARDBP The gene, called DNA methylation, appears to help increase levels and clumping of the TDP-43 protein in the motor cortex of people with amyotrophic lateral sclerosis (ALS), according to a study.

As methylation of this gene – which stops the cellular machinery from reading this gene and making proteins – decreases with age, study results begin to explain why advanced age is a major risk factor. for ALS.

Age-related demethylation of the TDP-43 self-regulatory region in the human motor cortex»Was published in the journal Nature Communications Biology.

In over 95% of sporadic cases of ALS, the TDP-43 protein forms abnormal clumps in motor neurons, the nerve cells that control muscle movement. This aggregation leads to loss of motor neurons in an area of ​​the brain called the motor cortex and symptoms of disease.

Aging is a risk factor for motor neuron loss and the development of ALS, and researchers believe there may be a link between age and higher levels of TDP-43. However, the exact mechanism linking this protein to aging and the impact on motor neurons is still unknown.

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The amount of TDP-43 is strictly controlled by how its messenger RNA – mRNA, the molecule that carries the instructions of the TARDBP gene to make the TDP-43 protein – is processed, via a mechanism called splicing.

Splicing essentially determines which parts of the gene are retained to be read by the protein manufacturing machinery. In the case of TARDBP, if too much TDP-43 protein is already in the nucleus, cells alter the splicing process to produce an mRNA molecule which is degraded and will not lead to protein production, thus helping to control TDP- levels. 43.

Since aging is associated with the loss of DNA methylation – the biological process by which methyl groups are added to DNA to suppress gene activity – researchers based at the University of Niigata in Japan wondered whether methylation of DNA from TARDBP genes change with age.

They also examined whether a change in methylation state could alter the splicing mechanism of TDP-43 mRNA to increase TDP-43 production in motor neurons, ultimately leading to aggregation and disease. .

“It’s a big mystery why TDP-43 selectively accumulates in the motor cortex as we age in ALS. TDP-43 accumulates as its amount increases, ”said Osamu Onodera, MD, PhD, director of the Brain Research Institute at the University of Niigata and lead author of the study, in a press release.

“However, TDP-43 itself is expressed in all cells, and the amount of TDP-43 in a cell is kept strictly constant through splicing,” Onodera added.

To find out, the researchers selectively demethylated the TARDBP gene to determine whether it affected TDP-43 expression and to study DNA methylation status in brain tissue collected post-mortem from seven patients with ALS and eight people without brain disease serving as a control group .

“Many neurological diseases, including ALS, have ‘aging’ as a risk factor. DNA methylation changes, which shape tissue specificity, are also affected by aging, which in turn affects splicing, ”said Onodera. “This is why we focused on methylation at the regulatory site of the TDP-43 gene.”

The team demonstrated that demethylation suppressed the correct splicing of TARDBP MRNA, with a 1.85-fold increase in unspliced ​​mRNA. In brain samples, the amount of DNA methylation in the cerebral cortex and cerebellum did not differ between ALS patients and controls.

In the motor cortex of the brain, however, control samples showed less methylation in TARDBP with advanced age. People in their 50s had about 80% DNA methylation, which fell to almost 50% in people in their 80s. Among older people, methylation was “extremely low,” the researchers noted.

No correlation between methylation and age was evident in patients with ALS. But their methylation levels were about 65% of those normally found at age 45, and similar to levels seen in people in their sixties and sixties.

Other experiments have shown that TARDBP expression tended to increase when DNA was demethylated in motor cortex samples, but this association was significant only in samples from the control group.

The researchers also measured the levels of TDP-43 protein in the tissues of the motor cortex. Although there was no association between DNA methylation levels and normally folded TDP-43 protein, less methylation was linked to more aggregated TDP-43.

Finally, they studied the relationship between TARDBP methylation in the motor cortex and clinical features of ALS patients. A significant correlation was found between less methylation in the TARDBP gene and age of onset of ALS, but not with the duration of the disease.

“Thus, the unique profile of TARDBP … DNA methylation in the motor cortex may contribute to susceptibility to TDP-43 pathology [disease] during brain aging in people with ALS, ”the researchers wrote.

“Regulation of methylation in the regulatory region of TDP-43 may provide a novel therapeutic approach for ALS,” said Onodera. “Tissue-specific and age-related methylation changes in disease-associated genes may also play a role in other neurodegenerative diseases.”

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