A Possible Path to Preventing TDP-43 Aggregation

TDP-43 is known to increase with age, and also forms aggregates observed in ALS and frontemporal dementia, among other conditions. The increased amount of TDP-43 alone, even without aggregates, appears to diminish the cellular housekeeping process of autophagy, with detrimental long term consequences. Artificially reducing the levels of TDP-43 too far will produce other issues, however, as this disrupts correct microglial function in the brain, making the microglia too aggressive when it comes to dismantling synaptic connections between brain cells. Thus building a therapy that targets TDP-43 isn't as straightforward as it might be. Here, researchers look at breaking down the aggregates rather than targeting TDP-43 indiscriminately, an approach that may result in a therapy for TDP-43-related conditions.

Scientists have long known that a protein called TDP-43 clumps together in brain cells of people with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, and is associated with neuron death. This same protein is thought to cause muscle degeneration in patients with sporadic inclusion body myositis (sIBM), leading many researchers to think that TDP-43 is one of the causative factors. Now, researchers found that a specific chemical modification called acetylation promotes TDP-43 clumping in animals. Using a natural anti-clumping method in mouse models, the scientists reversed protein clumping in muscle cells and prevented the sIBM-related muscle weakness. "We suspect that getting rid of this abnormal TDP-43 clumping could be a potential therapy for these diseases. In principle, we think this reversal of clumping could be achieved by taking an injectable or oral medication. Though, we caution, that's still a long way off. The research community still has much more work to do."

TDP-43 normally works in the cell nucleus. It binds to DNA and to the RNA molecules transcribed from DNA. The protein appears to have many important functions in regulating how genes are expressed. Somehow - in people with sIBM, ALS, and a few other degenerative diseases - TDP-43 moves out of the nucleus and into the main volume of the cell, or cytoplasm, and then clumps together. The loss of TDP-43 from the nucleus leads to the failure of normal gene expression regulation. Many scientists suspect that this is the major reason why affected cells die. For many years, no one knew how TDP-43 moved out of its normal workspace in the cell nucleus, but a 2015 study identified one possible factor: a chemical modification known as acetylation.

Cells commonly use acetylation to switch the activity of proteins on or off. Acetylation at two spots on TDP-43 caused the protein to detach from RNA. The protein then drifted into the cytoplasm and started to aggregate. This research was done in cells grown in lab dishes. To underscore the potential relevance to human disease, the scientists examined spinal motor neurons from ALS patients and identified aggregates of TDP-43 that had been acetylated in the same way. For the new study, the researchers examined the effect of acetylated TDP-43 in living animals. In this case, they sought to mimic sIBM in mice, in which TDP-43 clumps in muscle cells. "We tend to see sIBM and ALS as resulting from essentially the same TDP-43-related pathological process - the clumping effect - but in different cell types. The advantage of studying sIBM is that muscle cells are much more accessible than are motor neurons, which are affected in ALS."

The team used a special method to inject acetylated TDP-43 proteins directly into mouse muscle cells. In contrast to ordinary TDP-43 proteins, these acetylated proteins quickly aggregated outside the nucleus. The aggregate-burdened cells showed multiple features that are also seen in human sIBM. The researchers observed cellular markers indicating that the muscle cells were actively trying to get rid of the TDP-43 aggregates. The team found that they could boost these cell defense mechanisms and swiftly remove most of the aggregates by adding heat shock factor 1 (HSF1), a naturally occurring protein that is known to work as a master switch for anti-aggregation processes in cells. The researchers now hope to identify compounds suitable for use in oral drugs that have the same anti-clumping effect.

Link: https://www.eurekalert.org/pub_releases/2017-07/uonc-anc071417.php


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