A recent study highlights a previously unknown function of the TDP-43 protein in nerve cells that may contribute to the progression of amyotrophic lateral sclerosis (ALS). The finding adds a new layer of knowledge that could help to better understand the mechanisms involved in ALS development and progression.
TDP-43 protein regulates gene levels, but also ensures the correct DNA sequence is properly read. It is known to be deregulated in the majority of sporadic ALS cases and in many frontotemporal dementia cases.
Also, mutations on the TDP-43 protein-coding gene TARDBP have been linked to cases of familial ALS. This strongly suggests that TDP-43 contributes to the development of ALS, but its exact role is unclear.
In a study recently published in the journal Autophagy, Spanish researchers revealed that TDP-43 is an important regulator of a mechanism that cells normally use to keep themselves healthy, a process called autophagy.
The study is titled “Cryptic exon splicing function of TARDBP interacts with autophagy in nervous tissue.”
Previous studies have shown that in the absence of TDP-43, other proteins may become deregulated as so-called “cryptic exons” are included in their coding gene. These cryptic exons introduce a genetic sequence into the original sequence that promotes the production of shorter versions of the coded protein, which can ultimately impact a cell’s function and survival.
In this study, the research team focused their attention on the role of TDP-43 in regulating the levels of the ATG4B gene in ALS.
ATG4B encodes a critical mediator of autophagy. This is a cleaning system that ensures the destruction of a cell’s waste and damaged parts. Autophagy was shown to have a dual role in ALS by preventing disease progression in early stages and supporting its progression through the spinal cord in later stages.
The team analyzed brain and spinal cord tissue samples collected after death from eight patients who had typical manifestations of sporadic ALS and compared them with those of 17 age- and gender-matched controls.
They found that the loss of TDP-43 was associated with an increased amount of cryptic exons in the ATG4B genetic sequence. Also, levels of cryptic exon in ATG4B were found to be correlated with disease duration and the amount of abnormal ATG4B production. Patients with more severe ALS manifestations were found to have higher levels of aberrant ATG4B.
To further validate the role of TDP-43 in regulating ATG4B, the team genetically prevented the production of TDP-43 in human nervous cells. This led to an increase by about 20 percent of cryptic exons in ATG4B sequence, which induced a loss of 30 percent in the production of its coded protein.
Collectively, these results demonstrated that TDP-43 deficiency can affect autophagy in nerve cells by at least changing the normal readout of the ATG4B gene.
“The present data points to a novel mechanism implicating autophagy as a relevant factor” in the development of sporadic ALS, “in addition to the involvement of autophagy pathway” in familial ALS, the researchers noted.