TDP43 and Autophagy in Frontotemporal Dementia and ALS

Researchers have been looking into the biochemistry of TDP43 and failure of autophagy for a few years now in the context of some age-related dementias and amyotrophic lateral sclerosis (ALS). The processes of autophagy are cellular housekeeping mechanisms, acting to recycle damaged components and remove unwanted waste. More autophagy is shown to occur in connection with many of the presently known methods of slowing aging and extending life in laboratory animals. The research community has been slow off the mark to make inroads into the development of treatments based on enhanced autophagy, however - there is nowhere near as much interest and funding for this goal as for, say, the production of calorie restriction mimetic drugs.

Still here is one example of this approach gaining traction, though here the aim is to treat conditions in which autophagy is impaired in a specific way, through the presence of too much TDP43. It is unclear as to whether a treatment to reduce levels of TDP43 would be of any application to boosting autophagy in an undamaged metabolism.

Deep inside the brains of people with dementia and ALS, globs of abnormal protein gum up the inner workings of brain cells - dooming them to an early death. But boosting those cells' natural ability to clean up those clogs might hold the key to better treatment for such conditions. Though the team showed the effect worked in animals and human neurons from stem cells, not patients, their discoveries point the way to find new medicines that boost the protein-clearing cleanup process.

The researchers focused on a crucial cell-cleaning process called autophagy - a hot topic in basic medical research these days, as scientists discover its important role in many conditions. In autophagy, cells bundle unwanted materials up, break them down and push the waste products out. [The team] showed how the self-cleaning capacity of some brain cells gets overwhelmed if the cells make too much of an abnormal protein called TDP43. The found that cells vary greatly in how quickly their autophagy capacity gets swamped.

"Using [a] new visualization technique, we could truly see how the protein was being cleared, and therefore which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells. This allowed us to see that increased autophagy was directly related to improved cell survival." Longer-living, TDP43-clearing brain cells are theoretically what people with ALS and frontotemporal dementia need. But only further research will show for sure.


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